"Lois Kills Stewie" is the second part of a two-part episode of Family Guy that aired on November 11, 2007. Part one was "Stewie Kills Lois". Both parts later re-aired together as a 1-hour special on February 10, 2008. This episode features a crossover with American Dad!, Seth MacFarlane's sister project, when Stewie encounters Stan Smith and Avery Bullock at the CIA. It guest stars American Idol judges Simon Cowell, Paula Abdul and Randy Jackson as themselves, and Patrick Stewart reprising his American Dad! role as Bullock.
Composer Ron Jones was nominated an Emmy Award for his music for this episode, particularly during the battle between Stewie and Lois. This makes "Lois Kills Stewie" the first episode of Family Guy to be nominated for a Creative Arts Emmy Award for Outstanding Music Composition for a Series (Dramatic Underscore).
Peter is relieved that Lois is alive and asks her to tell her what happened tomorrow night since he has plans with his friends that night. Despite this, Lois reminds Peter that Stewie tried to kill her, and begins explaining what happened to her. Shortly after she was shot by Stewie and fell overboard, she was rescued and nursed back to life by a merman, which would have been romantic if he wasn't "the reverse of what you'd expect a merman to be". Awakening on a beach, Lois found herself suffering from amnesia with no memory of who she was. She found herself in North Carolina and wound up in a nearby fat camp, where she was hired as a counselor to keep the kids from eating each other. She entered a relationship with a man name Derek who eventually became comfortable enough to introduce her to his friends, who are all white supremacists. One of them ended up throwing a glass bottle at Lois' heads while she was promoting tolerance at their anti-Semite convention. This concussion completely restored her memory, and she rushed back to Quahog to where she is now. As soon as she finishes her story, everyone realizes that Stewie has escaped, so Joe initiates a manhunt to find him.
The Griffins return home to find Stewie waiting, armed with a gun. He is outraged that the Griffins never noticed how "messed up and evil" he was until now, and holds them hostage. Joe comes to the house to check on them, unaware of Stewie's presence, as Stewie makes Brian tell Joe everything's fine, as well as make fun of him. Later, an awkward moment involving Stewie trying to force Brian to test Lois' breast milk for poison is interrupted by Cleveland, whom Stewie shoots in front of the terrified family. Predicting that this will not be ignored ("'Black Man Gone Missing'; the media will be all over it!"), Stewie ties the family to chairs, stuffs Cleveland's body under the sofa cushions, and takes Brian with him to make a getaway in his car, as well as make fun of Joe again. While making up fake celebrity rumors to pass the time, the Griffins realize that Stewie forgot to tie Chris' arms down when he applauds this activity; Chris had kept quiet about this for the past 14 hours because he enjoyed the quality time spent with his family. They break free and search Stewie's room for clues as to where Stewie is going, but stumble upon his secret arsenal of weapons and other devices instead.
Stewie and Brian end up at the CIA Headquarters. Posing themselves as agents, Stewie takes Brian with him to the CIA's supercomputer, where he takes control of the planet's power grid and causes a worldwide blackout. Two agents, who turn out to be Stan Smith and Avery Bullock from the show American Dad!, intervene, but with the world's power at his mercy, Stewie coerces the helpless CIA into naming him "President of the World". Broadcasting from the Oval Office in the White House, Stewie begins concocting new laws such as making everyone throw apples at Peter when they see him, and tabooing the phrases "irregardless", "a whole 'nother", and "all of the sudden" under threat of being sent to a work camp. Fed up, Lois angrily declares that she must put an end to Stewie's reign of terror. Arming herself with Stewie's weapons, Lois sets out to kill Stewie.
Lois crashes through the window in the Oval Office and confronts Stewie while he's getting his Presidential portrait done. With Stewie also armed and readily dangerous, he and Lois clash in a drawn-out, bloody and action-packed deathmatch filled with gunplay, knife fighting, etc. Lois eventually gains the upper hand and prepares to shoot Stewie. Stewie spurs her on to kill him which, as she soon finds, she could never bring herself to do to her own baby. Stewie attempts to take the opportunity to finish her off himself but, before either of them know it, he is shot dead by Peter.
Shortly afterward, it is revealed that most of the events from the past two episodes were in fact a computer simulation Stewie was watching to see what would happen if he did try to kill Lois for leaving him behind on the cruise. Stewie states to Brian that his plans of world domination and killing Lois will have to wait. The two then enter a semi-meta debate regarding how people who would "theoretically" watch these events be "pissed off" to discover that none of them were real.
At Comic-Con, after doing a table read for the American Dad! episode "The 42-Year-Old Virgin", there was a Q&A. Someone asked Seth MacFarlane if there were plans to do an American Dad!/Family Guy crossover where the Griffins would meet the Smiths. MacFarlane said there is currently none in the works, but American Dad! characters would appear in a Family Guy episode. This is the one he was referring to.
The crossover of these two Seth MacFarlane shows takes place at the CIA where Stewie hacks into the global power grid the moment Stan and Bullock show up, only to have no choice but to make him the "President of the World".
Even though this two-parter is mostly non-canon, many consider this to be the first actual appearance of American Dad! characters in a Family Guy episode, not counting the brief appearances of Roger the Alien in the episodes "Meet the Quagmires" and "Blue Harvest".
Stewie's secret weapons room was discovered by Lois in another dream-like sequence in the episode "Mr. Griffin Goes to Washington"; ironically, this occurred in a dream Lois herself was having. As he trains his weapon on her, Stewie asks his mother to say hello to Mr. Weed for him, who died back in "Mr. Saturday Knight", which was written by Steve Callaghan, who also wrote this episode.