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Scion of a prominent Virginia family, Blair was born at Williamsburg in 1732. He was the son of John Blair, a colonial official and nephew of James Blair, founder and first president of the College of William and Mary. Signer Blair graduated from that institution and studied law at London's Middle Temple. Thereafter, he practiced at Williamsburg. In the years 1766-70 he sat in the Virginia House of Burgesses as the representative of William and Mary. From 1770 to 1775 he held the position of clerk of the colony's council.
An active patriot, Blair signed the Virginia Association of June 22, 1770, which pledged to abandon importation of British goods until the Townshend Duties were repealed. He also underwrote the Association of May 27, 1774, calling for a meeting of the colonies in a Continental Congress and supporting the Bostonians. He took part in the Virginia constitutional convention (1776), at which he sat on the committee that framed a declaration of rights as well as the plan for a new government. He next served on the Privy Council (1776-78). In the latter year, the legislature elected him as a judge of the General Court, and he soon took over the chief justiceship. In 1780 he won election to Virginia's high chancery court, where his colleague was George Wythe.
Blair attended the Constitutional Convention religiously but never spoke or served on a committee. He usually sided with the position of the Virginia delegation. And, in the commonwealth ratifying convention, Blair helped win backing for the new framework of government.
In 1789 Washington named Blair as an associate justice of the U.S. Supreme Court, where he helped decide many important cases. Resigning that post in 1796, he spent his remaining years in Williamsburg. A widower, his wife (born Jean Balfour) having died in 1792, he lived quietly until he succumbed in 1800. He was 68 years old. His tomb is in the graveyard of Bruton Parish Church.