Claude's son François de Lorraine, 2d duc de Guise, 1519–63, became conspicuous, at the accession (1547) of Henry II, as the rival for power of Anne, duc de Montmorency. In the final stages of the Italian Wars, François distinguished himself in the defense of Metz (1552), led the expedition to Italy against King Philip II of Spain, and after the failure of the expedition returned to defend France from English and Spanish attacks; in 1558 he took Calais from the English. With the accession (1559) of the youthful Francis II, who was married to the duke's niece, Mary Stuart, François de Guise and his brother the Charles de Guise, Cardinal de Lorraine, c.1525–1574, were given control of the government.
The brothers' arrogance, their persecution of the Protestants, and their enmity toward the princes of Bourbon and Condé led to the conspiracy of Amboise (see Amboise, conspiracy of), which they suppressed (1560). Shortly afterward, however, the death of Francis II deprived the Guises of power; Catherine de' Medici, as regent, dominated the government. As a result, in 1561 the duke joined with Montmorency and Marshal Saint-André in the so-called triumvirate, which, at the head of the Catholic party, opposed both the Huguenots and the tolerant policy of the regent. The murder of Protestants at Vassy by Guise's troops brought about the outbreak of the Wars of Religion (1562–98; see Religion, Wars of), and Guise took the field against the Huguenots. Victorious at Dreux (1562), he was assassinated while preparing to attack Orléans.
The Cardinal de Lorraine was largely responsible for the persecution of the Protestants during the reign of Francis II. At the Colloquy of Poissy (1561) he defended Catholicism against Theodore Beza; at the Council of Trent (1562–63) he at first upheld the independence of the Gallican church but later reversed his position and attempted to have the decrees of the council proclaimed in France. He subsequently negotiated with Philip II of Spain for Spanish support of the Catholic cause in France. After the downfall of Michel de L'Hôpital, Charles temporarily returned to power until 1570. He was the most consummate politician in his family and a master of intrigue.