James Blair became an Anglican clergyman, educational founder, and influential political figure in colonial Virginia. Educated in Scotland, he arrived in Virginia in 1685 and served as rector of Henrico Parish. Appointed commissary of the bishop of London, he represented ecclesiastical authority in the colony and worked among clergy, vestries, governors, and leading planter families.

Blair helped organize support for a college and traveled to England to obtain royal backing. The charter issued by William III and Mary II in 1693 established the College of William and Mary, with Blair as its first president. He sought funds, recruited teachers, developed statutes, and defended the institution against competing claims on colonial resources. Fire and financial difficulties required rebuilding, while later construction provided a chapel, library, and other facilities.

His position was political as well as educational. Serving for many years on the governor's council, he challenged governors including Edmund Andros, Francis Nicholson, and Alexander Spotswood and helped secure their removal. Disputes involved authority, patronage, church affairs, and the college. Blair's alliances with influential families strengthened his position, while his confrontational methods repeatedly divided colleagues and clergy.

He also served parishes around Jamestown and Williamsburg and published sermons. The college he led trained the colony's governing elite and included an Indian school intended to advance Anglican and colonial purposes. Its operation existed within a plantation society sustained by slavery, and Blair himself accumulated property and enslaved people. As senior councillor, he briefly acted as chief executive during Governor Gooch's absence in 1740–1741. He retained his offices until death in 1743, though age limited his activity. His persistence helped William and Mary survive, while his religious and political authority reflected colonial Virginia's unequal institutions.