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As the American Revolution approached, Henry became one of Virginia's leading advocates for independence. He helped create the First Continental Congress, and in 1774 won the election to that body representing Virginia. he urged his fellow Virginians to arm themselves and reportedly underscored his remarks with a statement that would resonate for generations, "I know not what course others may take; but as for me, give me liberty or give me death."

When the Revolution began in earnest, Henry briefly led the Virginia militia before winning the first of his five terms as Virginia's governor in 1776. After the war, Henry championed the cause of states' rights and lobbied unsuccessfully against the ratification of the United States Constitution. A staunch Anti-Federalist, he turned down George Washington's offer to become Secretary of State because of the President's strong Federalist leanings. Henry eventually reversed his position and supported American efforts to develop a strong central government.