George Grenville replaced his friend the Earl of Bute in 1763. However, he did not have the full confidence of the King and had a powerful enemy in Pitt the Elder. His premiership was full of problems. His prosecution of MP John Wilkes for seditious libel against the King and Bute made him unpopular as people assumed he was trying to muzzle the press.
He attempted to regain favour by lowering domestic taxes at the expense of the colonies, introducing the Stamp Act in 1765. The laws gave rise to widespread protests in America that eventually boiled over into the War for Independence.
Grenville's fate was sealed when he fell out with the King over who should rule for the King in the event of a deterioration of his mental health - Grenville tried to remove Queen Caroline, the King's mother, from the list because of her friendship with the Earl of Bute. It led to the King uncermoniously sacking him in 1765.