Sir William Kirkcaldy of Grange was the son of Sir James Kirkcaldy, Lord High Treasurer under James V. His mother was Janet Melville sister of the five Melville brother who played such a prominent part as civil servants and diplomats during the reign of Mary Queen of Scots. He first came to notice in 1546 during the conspiracy against Cardinal David Bethune, when a group of Fife lairds entered the castle at St Andrews bent on killing him.