Frist joined the lab of W. John Powell Jr., M.D. at Massachusetts General Hospital in 1977, where he continued his training in cardiovascular physiology. He left the lab in 1978 to become a resident in surgery at Massachusetts General Hospital. In 1983, he spent time at Southampton General Hospital, Southampton, England as senior registrar in cardiothoracic surgery. He returned to Massachusetts General in 1984 as chief resident and fellow in cardiothoracic surgery. From 1985 until 1986, Frist was senior fellow and chief resident in cardiac transplant service and cardiothoracic surgery at the Stanford University School of Medicine. After completing his fellowship, he became a faculty member at Vanderbilt University Medical Center, where he began a heart and lung transplantation program. He also became staff surgeon at the Nashville Veterans Administration Hospital. In 1989, he founded the Vanderbilt Transplant Center. In 1991, Dr. Frist operated on then-Lieutenant Colonel David Petraeus after he'd been shot in an incident of accidental fratricide.
He is currently licensed as a physician, and is board certified in both general surgery and thoracic surgery. He has performed over 150 heart transplants and lung transplants, including pediatric heart transplants and combined heart and lung transplants.
In 1990, Frist met with former Senate Majority Leader Howard Baker about the possibilities of public office. Baker advised him to pursue the Senate, and in 1992 suggested that Frist begin preparations to run in 1994. Frist began to build support. He served on Tennessee's Governor's Medicaid Task Force from 1992 to 1993, joined the National Steering Committee of the Republican National Committee's Health Care Coalition, and was deputy director of the Tennessee Bush-Quayle '92 campaign. As part of Frist's preparations for political office, in December 1993 he ended his membership in Nashville, Tennessee's racially segregated Belle Meade Country Club, which he had joined in the 1980s, (following a family tradition).
During his first campaign, Frist repeatedly accused his opponent, incumbent Senator Jim Sasser, of "sending Tennessee money to Washington, DC, to Marion Barry ... While I've been transplanting lungs and hearts to heal Tennesseans, Jim Sasser has been transplanting Tennesseans' wallets to Washington, home of Marion Barry." During that campaign, he also attacked Sasser for his attempt to become Senate Majority Leader, claiming that his opponent would be spending more time taking care of Senate business than Tennessee business; an ironic claim to make given that Frist himself would become Majority Leader some years later. Frist won the election, defeating Sasser by 13 points in the 1994 Republican sweep of both Houses of Congress, thus becoming the first physician in the Senate since June 17, 1938, when Royal S. Copeland died.
In his 2000 reelection campaign, Frist easily won with 66 percent of the vote. He received the largest vote total ever by a statewide candidate in the history of Tennessee, although Al Gore won a higher percentage of the vote (70%) in his 1990 Senate re-election. Frist's 2000 campaign organization was later fined by the Federal Election Commission for failing to disclose a $1.44 million loan taken out jointly with the 1994 campaign organization.
As the chairman of the National Republican Senatorial Committee, he helped Republicans win back the Senate in the 2002 midterm election. His committee collected $66.4 million for 2001–2002, 50% more than the previous year. Shortly afterwards, Sen. Trent Lott made comments at a Strom Thurmond birthday celebration in which he said that if Thurmond's presidential bid of 1948 had succeeded, "we wouldn't have all these problems today". In the aftermath, Lott resigned his position as Senate Majority Leader and Frist was chosen unanimously by Senate Republicans as his replacement. He became the second youngest Senate Majority Leader in US history. In his 2005 book, "Herding Cats, A Lifetime in Politics", Lott accuses William Frist of being "one of the main manipulators" in the debate that ended Senator Lott's leadership in the Republican Senate. Lott wrote that Senator Frist's actions amounted to a "personal betrayal." Frist "... didn't even have the courtesy to call and tell me personally that he was going to run ... If Frist had not announced exactly when he did, as the fire was about to burn out, I would still be majority leader of the Senate today," Lott wrote.
In the 2003 legislative session, Frist enjoyed many successes. He was able to push many initiatives through to fruition, including the Bush administration's third major tax cut and legislation that was against partial-birth abortion. However, the tactics that he used to achieve those victories alienated many Democrats. In 2004, by comparison, he saw no major legislative successes, with the explanations ranging from delay tactics by Democrats to lack of unity within the Republican Party.
In a prominent and nationally broadcast speech to the Republican National Convention in August 2004, Frist highlighted his background as a doctor and focused on several issues related to health care. He spoke in favor of the recently passed Medicare prescription drug benefit and the passage of legislation providing for Health Savings Accounts. He described President Bush's policy regarding stem cell research, limiting embryonic stems cells to certain existing lines, as "ethical." In an impassioned argument for medical malpractice tort reform, Frist called personal injury trial lawyers "predators": "We must stop them from twisting American medicine into a litigation lottery where they hit the jackpot and every patient ends up paying." Frist has been an advocate for imposing caps on the amount of money courts can award plaintiffs for noneconomic damages in medical malpractice cases.
During the 2004 election season, Frist employed the unprecedented political tactic of going to the home state (South Dakota) of the opposition party (Democrat)'s minority leader, Democrat Tom Daschle, and actively campaigned against him. Daschle's Republican opponent, John Thune, defeated Daschle. In Daschle's farewell address, Frist arrived late. After the 2004 elections, Frist played a role in the controversy over Arlen Specter's post-election remarks. Frist demanded a public statement from Specter in which Specter would repudiate his earlier remarks and pledge support for Bush's judiciary nominees. Frist rejected an early version of the statement as too weak, and gave his approval to the statement that Specter eventually delivered.
Frist received some criticism within the Republican caucus in the Senate over his handling of the Majority Leader position, and his near invisibility as a spokesman for the Republican caucus, which has damaged his reputation. His supporters within the caucus point to his success in moving tax legislation important to the executive branch as a sign that he is simply filling his place on the team, namely to bring important bills to a vote, and then ensure that gains made on the floor are preserved in the conference committee process.
Many of Frist's opponents have attacked him for what they see as pandering to future Republican primary voters. They claim that he has taken extreme positions on social issues such as the Terri Schiavo matter in order to please them. On the other hand, Frist changed his position on stem cell research.
There has also been controversy regarding the "nuclear option," under which the Republicans would change a rule in the Senate to prevent the filibuster of judicial nominations. Although Frist claimed that "[n]ever before has a minority blocked a judicial nominee that has majority support for an up-or-down vote on the Senate floor," critics pointed to the nearly two century history of the filibuster, including the successful four-day 1968 minority Republican filibuster of Lyndon Johnson's chief justice nominee, Abe Fortas. Also, in 1998 Frist participated in the Republican filibuster to stall the nomination of openly gay James C. Hormel to be ambassador to Luxembourg; Hormel eventually received a recess appointment from President Bill Clinton, bypassing a Senate vote. Frist also helped block the 1996 nomination of Richard Paez to the 3rd Federal Court of Appeals, a four-year filibuster that was defeated in 2000 when 14 Republicans dropped their support for it and allowed Paez to be confirmed by a simple majority.
More criticism of perceived weakness came in the midst of an extended confirmation fight over Bush's pick for US ambassador to the United Nations, John R. Bolton. Twice Frist failed to garner the 60 votes to break cloture, getting fewer votes the second time and even losing the support of one conservative Republican (George Voinovich of Ohio). On June 21, 2005, Frist said the situation had been "exhausted" and there would be no more votes. Only an hour later, after speaking to the White House, Frist said: "The president made it very clear he wants an up-or-down vote." This sudden switch in strategy led to charges of flip-flopping in response to pressure from the Bush administration. Nevertheless, no up-and-down vote was held, and Bush made a recess appointment of Bolton.
In September 2006, working with Arizona Senator Jon Kyl, Frist was a major Senate supporter of H.R. 4411 — the Unlawful Internet Gambling and Enforcement Act. Frist's bill called for the illegalization of online gambling, while Frist has received contributions from land-based casinos. He also allowed horse racing and lotteries to remain legal.
Frist pledged to leave the Senate after two terms in 2006, and did not run in the 2006 Republican primary for his Senate seat. He campaigned heavily for Republican nominee Bob Corker, who won by a small margin over Congressman Harold Ford, Jr. in the general election.
Frist had been widely seen as a potential presidential candidate for the Republican party in 2008, much in the same tradition as Bob Dole, a previous holder of the Senate Majority Leader position. On November 28, 2006, however, he announced that he had decided not to run, and would return to the field of medicine.
Frist's name has been frequently mentioned as a possible candidate for Governor of Tennessee in 2010 when incumbent Governor Phil Bredesen will be barred from running again due to term limits. Though no official word has come from Frist on the subject, Tennessee Republican Party Chairman Bob Davis has said that "he'd have a lot of support" if he chose to run. He has also been mentioned as a possible candidate for Chancellor of Vanderbilt University.
In June, 1989, Frist published his first book, Transplant: A Heart Surgeon's Account of the Life-And-Death Dramas of the New Medicine, in which he wrote, "A doctor is a man whose job justifies everything . . . Life [is] a gift, not an inalienable right."
With J. H. Helderman, he edited "Grand Rounds in Transplantation" in 1995. In October, 1999, Frist co-authored Tennessee Senators, 1911–2001: Portraits of Leadership in a Century of Change with J. Lee Annis, Jr. In March, 2002, Frist published his third book, When Every Moment Counts: What You Need to Know About Bioterrorism from the Senate's Only Doctor. While generally well received, the book later spurred accusations of hypocrisy regarding his remarks about Richard Clarke. When Clarke published his book Against All Enemies in 2004, Frist stated "I am troubled that someone would sell a book, trading on their service as a government insider with access to our nation's most valuable intelligence, in order to profit from the suffering that this nation endured on September 11, 2001." In December, 2003, Frist and co-author Shirley Wilso released Good People Beget Good People: A Genealogy of the Frist Family.
In 1998 he visited African hospitals and schools with the Christian aid group Samaritan's Purse. Frist has continued to make medical mission trips to Africa every year since 1998. He has also been vocal in speaking out against the genocide occurring in Darfur. He is currently teaching a course on health care policy at Princeton University.
Frist has a fortune in the millions of dollars, most of it the result of his ownership of stock in Hospital Corporation of America, the for-profit hospital chain founded by his brother and father. HCA paid over $1.7-billion in criminal penalties for Medicare fraud. Frist's 2005 financial disclosure form lists blind trusts valued between $15 million and $45 million.
Members of the Frist family have been major donors to Princeton University, pledging a reported $25 million in 1997 for the construction of the Frist Campus Center. Frist has said that, a few years after his 1974 graduation from Princeton, "I made a commitment to myself that if I was ever in a position to help pull together the resources to establish a center [on the Princeton campus] where there could be an informal exchange of ideas, and to establish an environment that is conducive to the casual exchange of information, I would do so. Daniel Golden, a Wall Street Journal journalist and author of the book The Price of Admission: How America's Ruling Class Buys Its Way into Elite Colleges — and Who Gets Left Outside the Gates, has suggested that two of Frist's sons (Harrison and Bryan) were admitted to Princeton as recognition of this donation rather than their own academic and extracurricular merit.
Frist and his wife are the sole trustees in charge of a family foundation bearing the senator's name, which had more than $2 million in assets in 2004. Frist and his siblings are vice presidents of another charitable foundation bearing their parents' names. Frist failed to list his positions with the two foundations on his Senate disclosure form. In July 2006, when the matter was raised by the Associated Press, his staff said the form would be amended. Frist has previously disclosed his board position with World of Hope, a charity that gives money to causes associated with AIDS. The charity has come under scrutiny for paying consulting fees to members of Frist's political inner circle.
The status of Frist’s blind trust, and subsequent statements about it and activities within it led to an SEC Investigations of the trustees June 13th 2005 sale. The U.S. Attorney for the Southern District of New York issued subpoenas to investigate the sale, and the U.S. Securities and Exchange Commission began an insider trading investigation of the sale. After an 18 month investigation, Frist was cleared of any wrongdoing saying that "I've always conducted myself according to the highest ethical standards in both my personal and public life, and my family and I are pleased that this matter has been resolved,"
Frist supports a total ban on human cloning, including for embryonic stem cell research. Since 2001, Frist had stood beside Bush in his insistence that only currently existing lines be used for stem cell research. But in July 2005, after severely criticizing the MLO, Frist reversed course and endorsed a House-passed plan to expand federal funding of the research, saying "it's not just a matter of faith, it's a matter of science. Up to that point the legislation had been considered bottled up in the Senate. The decision quickly drew criticism from some Christian groups such as Dr. James Dobson, but garnered praise from some Democrats and many Republicans, including former First Lady Nancy Reagan.
On education, Frist supports the No Child Left Behind Act, which passed in 2001 with bipartisan support. In August 2005 he announced his support for teaching intelligent design in public school science classes.
In November 2005, Frist told reporters that he was less concerned about possible torture at CIA secret prisons than he was about potentially compromising the security of millions of Americans. Flying home after visiting the Guantanamo Bay detention center he said September 10 2006 he expects bipartisan support for putting top captured al-Qaida figures on trial before military commissions and for guidelines on how they should be treated. Frist visited the detention center in eastern Cuba, which holds some 460 detainees, including 14 top alleged al-Qaida figures recently transferred from CIA custody. Frist said his visit with fellow Republicans Sen. Mitch McConnell of Kentucky and Sen. Arlen Specter of Pennsylvania, the Senate Judiciary Committee chairman, was especially poignant coming one day short of the fifth anniversary of the attacks that killed nearly 3,000 people. Frist told that to be there with the recognition that 14 individuals were there who in all likelihood contributed to the September 11, 2001 attacks led him to think how critical it is that we do define the appropriate criteria to make sure we get information to prevent such a tragedy from ever occurring again. The senators didn't see the 14 new detainees and instead visited Guantanamo to learn of interrogation techniques he said. In his mind, the detainees are being treated in a safe and humane way.