Born in Rockbridge County, Virginia, Houston and his family relocated to Maryville, Tennessee, when he was a teenager. Houston later ran away from home, spending about three years living with the Cherokee, becoming known as "Raven." He served under General Andrew Jackson in the War of 1812; afterwards, and despite his earlier connections to the Cherokee people, he presided over the mass removal of Cherokee from Tennessee. With the support of Jackson, among others, Houston won election to the United States House of Representatives in 1823. He strongly supported Jackson's presidential candidacies and, in 1827, Houston was elected as the governor of Tennessee. In 1829, after divorcing his first wife, Houston resigned from office, and moved to the Arkansas Territory.
His Senate record was marked by his unionism and opposition to radicals from both the North and South. He voted for the Compromise of 1850, which settled many of the residual territorial issues from the Mexican–American War and the annexation of Texas. Houston owned slaves throughout his life. He voted against the Kansas–Nebraska Act, as he believed it would lead to increased sectional tensions over slavery, and his opposition to that act led him to leave the Democratic Party. He was an unsuccessful candidate for the presidential nomination of the American Party in the 1856 presidential election, as well as for the Constitutional Union Party in the 1860 presidential election. In 1859, Houston won election as the governor of Texas. In this role, he opposed secession, but unsuccessfully sought to keep Texas out of the Confederate States of America. He was forced out of office in 1861, and died two years later in 1863. Houston's name has been honored in numerous ways, and he is the eponym of the city of Houston, the fourth-most-populous city in the United States.