The 3rd Duke of Devonshire, like his father and grandfather, was active in politics. He was a Member of Parliament from 1721 until his father's death sent him to the House of Lords in 1729.

He was made a Privy Counsellor in 1731. He served as Lord Privy Seal from 1731 to 1733, when he was invested as a Knight of the Garter. He later served for seven years as Lord Lieutenant of Ireland.

The Prime Minister, Sir Robert Walpole, was a friend of his and his father, and the Van Dyck portrait of Arthur Goodwin which hangs in the Great Dining Room at Chatsworth came from Walpole's collection.

The 3rd Duke married Catherine Hoskins (1700-1777) in 1718, and together they had seven children.

On 16 October 1733, Devonshire House, the London residence of the Dukes of Devonshire, was destroyed by fire. The 3rd Duke commissioned William Kent to rebuild and furnish the house in the Palladian style. Much of the furniture designed by Kent is now at Chatsworth, following the sale and demolition of Devonshire House in 1924.

The 3rd Duke died in 1755 and was succeeded by his eldest son William.

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