The House of Guise was founded as a cadet branch of the House of Lorraine by Claude de Lorraine, first Duke of Guise (1496-1550), who entered French service and was made a duke by King François I. Claude's daughter, Mary of Guise (1515-1560), married King James V of Scotland and was mother of Mary Queen of Scots. Claude's eldest son, François, became a military hero thanks to his capture of Calais from the English in 1558.
In 1558, King François II, married Mary Queen of Scots. By 1559, she had her two powerful uncles of the House of Guise appointed to high positions in the French government. This prompted the Amboise conspiracy in which the Huguenots and the House of Bourbon plotted to usurp the power of the House of Guise. The Duke of Guise and his brother, Charles, Cardinal of Lorraine, in his powerful capacity as a Cardinal of the Roman Catholic Church, controlled French politics during the short reign of the sickly young king, François II. The Cardinal of Lorraine was also leader of the French representatives at the final sittings of the Council of Trent, and, ironically given his family's role in French politics, had fought for a greater willingness to compromise with Protestantism than the Italian and Spanish delegates.
Championing Catholicism against the Huguenots, in 1560, the Guise family brutally put down the Conspiracy of Amboise. After King François' death they opposed the more tolerant policy of the Regent, Catherine de' Medici, and their doings provoked the French Wars of Religion.
The House of Guise, led by François, defeated the Huguenots at the battle of Dreux, but he was assassinated shortly afterward, in 1563. His son, Henri de Lorraine, became the third Duke of Guise (1550-1588). He helped plan the infamous St. Bartholomew's Day Massacre and was responsible for the formation of the Catholic League. The death of the heir-presumptive, the Duc d'Anjou, in 1584, which made the Protestant King Henry of Navarre heir to the French throne, led to a new civil war, the War of the Three Henries, with King Henry III, Henry III of Navarre, and Henry of Guise all fighting for control of France. Guise began the war by declaring the unacceptability of Navarre as King, and his control of the powerful Catholic League soon forced the King to follow in his wake. Immensely ambitious, in 1588 Guise, with Spanish support, instigated a revolt against the king, taking control of the city of Paris and becoming the de facto ruler.
After an apparent conciliation, in December of 1588 King Henri III had both the Duke of Guise and his brother, Louis de Lorraine, Cardinal of Guise (1555–1588), murdered during a meeting in the Royal Chateau at Blois. Leadership of the Catholic League fell to their brother, Charles of Lorraine, Duke of Mayenne who was commander of the armed forces of the Catholic League.
After King Henri III had his brother murdered, the Duke of Mayenne became head of the Catholic League. His nephew, the young Duke of Guise, was proposed by the Catholic League as a candidate for the throne, possibly through a marriage to Philip II of Spain's daughter Isabella, the granddaughter of Henry II of France. Although Mayenne and other members of the House of Guise had murdered, tortured and wreaked havoc on the lives of many French citizens, for the sake of the country King Henri IV bought peace with him and in January of 1596 a treaty was signed that put an end to the League.
The senior line of the Dukes of Guise became extinct in 1688.