When the young man became king after his father's death in 1559, the queen's uncles, the Duke of Guise and his brother the Cardinal of Lorraine, controlled French politics during his short reign.

In March 1560, opposition to the Guise government coalesced into a conspiracy, led by La Renaudie with support from the Bourbon Prince de Condé.

[3] Still incensed at his involvement in Amboise, the Guise called the Prince of Condé to them and oversaw a quick trial to establish his guilt, only for the death of Francis II and the succession of Charles IX to sever their links to the government.

[4] With Catherine assuming the regency for her young son, the Guise departed court and set themselves up in opposition to her toleration policy in alliance with their rival the Montmorency.

[6] Duke Francis helped to defeat the Huguenots at the Battle of Dreux (19 December 1562), but he was assassinated at the Siege of Orleans on 24 February 1563 while he was seeking a final victory.

[7] His son, Henry, inherited his titles; and under the direction of his uncle Charles began a campaign to accuse Admiral Coligny of orchestrating his fathers assassination.

[11] By the termination of the third war, the Guise would once more find themselves in disgrace from court due both to their hawkish policy and Henry's affair with Margaret de Valois.

[13][14] Having returned to favour, Henry helped plan the assassination of Coligny, the final culmination of his feud that would spiral into the St. Bartholomew's Day Massacre of the Huguenots in 1572.

In 1588 Guise, with Spanish support, instigated a revolt against the king, took control of the city of Paris and became the de facto ruler of France.