A branch of the ducal house of Lorraine that rose to prominence in 16th-century France. Claude de Lorraine (1496–1550) was created duke in 1528; he had distinguished himself in a number of French military victories, including Marignano (1515). Francis (1519–63), his son and heir, became the most effective commander in the armies of Henry II. He was active throughout the 1550s, capturing Calais from the English (1558) and helping to bring about the Peace of Cateau-Cambrésis in 1559. His brother Charles (1524–74) became Cardinal of Lorraine in 1550, and his sister Mary (1515–60) married James V of Scotland and was the mother of Mary, Queen of Scots.

In 1559, on the accession of Francis II, the Catholic Guise family was the most influential in France. Its dealings with the Huguenots and Bourbons (1559–62) led directly to the outbreak of the French Wars of Religion. Francis was assassinated in 1563. His son Henry (1550–88), the third duke, fought in the third and fourth wars, and was one of the instigators of the St Bartholomew’s Day Massacre. In 1576 he took the lead in organizing the Holy League, but Henry III had him assassinated in 1588, when he was being put forward as a possible heir to the throne. His brother, Charles (1554–1611), kept the Guise and extremist Catholic causes alive until 1595, when he submitted to Henry IV. The Guise ducal line died out in 1688.