When Charles James Fox seceded from the House of Commons, Tierney emerged as one of the most prominent opponents of William Pitt's foreign policy.

On the death of Fox in 1806 he joined William Grenville's Ministry of All the Talents as President of the Board of Control, with a seat in the cabinet, and thus brought himself once more into line with the Whigs.

About a year after the death of George Ponsonby in 1817, Tierney reluctantly became the recognised leader of the opposition in the House of Commons.

This motion was defeated by 357 to 178, which was a division involving the largest number of MPs until the debates over the Reform bill in the early 1830s.

In George Canning's ministry, he was Master of the Mint, and when Lord Goderich succeeded to the lead Tierney was admitted to the cabinet; but he was already suffering from ill-health and died suddenly at Savile Row, London.