During the Scottish Reformation, Châtellerault joined the Protestant Lords of the Congregation to oppose the regency of Mary of Guise, and lost his French dukedom as a result.

His father's family descended from Walter FitzGilbert, the founder of the House of Hamilton,[2] who had received the barony of Cadzow from Robert the Bruce.

[3] James's mother was the daughter of Sir David Beaton of Crich, the widow of Robert Livingstone of Easter Wemyss, and the second wife of the 1st Earl of Arran.

[24] In 1543, supporters of Matthew Stewart, 4th Earl of Lennox, challenged Arran's claim and legitimacy by suggesting that his father's divorce and second marriage were invalid.

In 1543 he helped to negotiate the marriage of the young Queen Mary to Edward, son of King Henry VIII of England, who had broken with Rome.

On 18 March 1543, Sir George Douglas of Pittendreich, brother of Lord Angus, told the English ambassador, Ralph Sadler, that: "if there be any motion now to take the Governor from his state, and to bring the government of this realm to the king of England, I assure you it is impossible to be done at this time.

For, there is not so little a boy but that he will hurl stones against it, and the wives will handle their distaffs, and the commons universally will rather die in it, yea, and many noblemen and all the clergy be fully against it.

[30][31] A seven-year war with England now called the Rough Wooing followed, which was declared on 20 December 1543, and signed by Arran the following month.

Arran replied that the parliament was dissolved, and so he thought it expedient not to answer Henry VIII on the points raised at the time.

"[37] In September 1547 Arran assembled a large Scottish army to resist an English invasion led by Edward Seymour, Duke of Somerset but was defeated at the battle of Pinkie.

For two weeks in February 1548, Arran led a campaign in Teviotdale with Monsieur d'Essé to recapture Ferniehirst Castle and punish borderers.

[40] Arran reluctantly agreed in July 1548 to Mary's marriage to Francis, eldest son of King Henry II of France.

Henry II rewarded him by making him Duke of Châtellerault on 8 February 1549 and a knight of the Order of Saint Michael.

He changed his allegiance in August 1559, joining the Protestant Lords of the Congregation to oppose the regency of Mary of Guise, and lost his French dukedom as a result.

In order to discredit him with the English government a letter was forged by his enemies, in which Châtellerault declared his allegiance to Francis II of France, but the plot was exposed.

[44] After the death of Mary of Guise on 15 June 1560, Châtellerault persuaded the Parliament of Scotland to back a plan to marry his son James to Elizabeth I, and then after the death of Francis II on 5 December 1560, he attempted, without success, to arrange for James to marry the young widowed Queen Mary.