He was a leading Parliamentarian during the English Civil War and worked closely with Oliver Cromwell. He played no part in the execution of King Charles I, and refused to take oaths that expressed approval of the act. Vane served on the Council of State that functioned as the government executive during the Interregnum, but split with Cromwell over issues of governance and removed himself from power when Cromwell dissolved Parliament in 1653. He returned to power during the short-lived Commonwealth period in 1659–1660. His fight for government reform, a constitution along with civil and religious liberties made him a man "Too Dangerous to Let Live" in King Charles' II view. Therefore, he was arrested under orders from King Charles II following his restoration to the throne. After long debate, Vane was exempted from the Indemnity and Oblivion Act, and was thus denied amnesty granted to most people for their roles in the Civil War and Interregnum.