During the United States Civil War, John Breckinridge became the only former vice president (1857–61) to ever go to war against the United States government.

Breckinridge was commissioned as a brigadier general in the Confederate Army on November 2, 1861. He was given command of the 1st Kentucky Brigade which was nicknamed the Orphan Brigade because its men felt orphaned by Kentucky's Unionist state government. This brigade was in the 2nd Division of the Army of the Mississippi, commanded by General Albert Sidney Johnston.

In 1862, Breckinridge's performance earned him a promotion to major general. After his promotion, he joined General Earl Van Dorn near Vicksburg, Mississippi.

After fighting in numerous battles for several years, Breckinridge was appointed Confederate Secretary of War on January 19, 1865. By late February 1865, Breckinridge concluded that the Confederate cause was hopeless. Ultimately, he was the person who disbanded the Confederate War Department.

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