The eldest daughter of Claude, Duke of Guise, head of the French House of Guise, and his wife Antoinette of Bourbon, Marie was married at the age of 19 to Louis of Orleans, Duke of Longueville. They had one son, Francis, before Marie's husband died in June 1537; their second son was born posthumously but did not survive.
In 1538 Marie married King James V of Scotland, himself a widower whose first wife had died two months after their wedding in 1537. James and Marie had two sons, but James lived less than a year, and Robert only two days. Their daughter Mary was born on December 8, 1542, and James died six days later, making Mary queen.
It was Marie of Guise who effectively ruled Scotland as Regent for Queen Mary, whom Marie sent to France when Mary was 5 years old, to be raised with her husband-to-be, the son of the French king. Marie always consulted with her two powerful brothers in France -- Charles, Cardinal of Lorraine, and Francis, Duke of Guise, both of whom held government positions -- so that Scotland and France worked as allies in dealing with other nations.
Marie's regency was threatened, however, by the growing influence of the Scottish Protestants, who effectively deposed her on religious grounds. When Marie died in June 10 or 11, 1560, her body was taken back to France and interred at the church in the Convent of Saint-Pierre in Reims, where Marie's sister Renée was the abbess.