Born in New York City into a wealthy and socially preminent family, Welles was educated at Harvard University, graduating in 1914. At a loss fo a career, Welles followed the advice of family friend Franklin D. Roosevelt and took the Foreign Service examination in 1915. He served briefly as US ambassador to Cuba in 1933, but his public and controversial atempts to undermine a liberal regime there led to his ouster.

In 1937 he was promoted to Undersecretary of State and was one of Roosevelt's most trusted diplomatic advisers, playing a leadership role in the formation of the North Atlantic Treaty Organization (NATO) in 1941. Welles was the natural choice to succeed the aging Secretary of State, but Hull's personal dislike made the president particularly receptive to rumors that Welles had frequently propositioned men for sex.

An official investigation initiated by FBI Director J. Edgar Hoover turned up evidence. Roosevelt, who personally disliked homosexuals, had no choice but to accept the resignation of his trusted friend and adviser. Excluded both formally and informally from foreign policy establishment, Welles lived quietly until his death.

Welles married three times, raised children and always denied any interest in homosexuality. His heavy drinking and preference for anonymous encounters reveal a deeply troubled sexual identity.