Guise was the son of Claude of Guise and his wife Antoinette of Bourbon. His sister Mary of Guise was wife of James V of Scotland and mother of Mary I of Scotland.
He led the French to victory over Germany at Metz in 1552 and captured Calais from the English in 1558. Along with his brother Charles of Guise he was powerful in the government of France during the reign of Francis II.
Guise was one of the leaders of the Catholic faction in the French Wars of Religion, and his massacre of Huguenots at Wassy-sur-Blaise on March 1, 1562 marked the starting point of that conflict.
He was shot by a Huguenot fanatic at the siege of Orleans on February 18, 1563 and died of his wounds a few days later.
He was succeeded by his son, Henry, 3rd Duke of Guise.
