Henry Clay was born in Hanover County, Virginia, on April 12, 1777. His father was a reverend who passed away when Henry was young, and after his mother remarried, the family moved to Richmond when he was fourteen. There he began to study law under the tutelage of George Wythe, a highly influential professor who also taught John Marshall, Thomas Jefferson, and James Monroe. Clay was admitted to the Virginia bar in 1797 and moved to Lexington, Kentucky, to open a law practice.

In Kentucky, he quickly established himself as one of the state's leading attorneys and began to pursue a political career. He was selected to finish unfulfilled Senate terms in 1806 and 1810 and, in between these brief tenures, served in the Kentucky state legislature. In 1810, he was elected to the U.S. House of Representatives and, on his first day there in November 1811, he was elected Speaker of the House. Previously the Speaker had primarily been a position to keep order and enforce rules, but Clay transformed it into a position of power. As leader of the Democratic-Republicans, he helped pressure James Madison into declaring war on Britain in 1812. In 1814, he resigned from the House to serve as one of the peace commissioners to negotiate a treaty with Britain to end the War of 1812. Upon his return to Congress, he was reelected Speaker and served in that capacity for nine more years.

Clay ran for President in 1824 and played a pivotal part in the controversial election. Andrew Jackson finished first in the initial round of voting but failed to capture a majority of electoral votes, meaning the House was charged with deciding the election. Clay threw his support behind second-place finisher John Quincy Adams and helped build support for him in Congress. Adams won the election and named Clay his secretary of state shortly thereafter. Many partisans suspected Adams and Clay had made a "corrupt bargain." These allegations followed Clay throughout his tenure as secretary which, in spite of his prior diplomatic experience, was generally unsuccessful. Secretary Clay's primary accomplishment was work on a number of commercial treaties, including agreements with a number of Latin American countries who had recently gained independence. He attempted to arrange U.S. participation in the Inter-American Congress in 1826 but was unsuccessful. He also sought to address lingering disputes with Mexico and Britain, but encountered frustrations in these endeavors as well. While his term as secretary appeared relatively undistinguished, Clay's emphasis on the economic interests of the country was a theme that would become an increasingly important part of U.S. foreign policy in the future. Ultimately, however, Clay was more suited for the legislative branch as opposed to the executive branch. His abilities in debate, oratory, and compromise found limited expression in his executive position. Additionally, the continued political attacks on his character and various personal problems, including a lengthy illness, made his tenure difficult. President Adams was defeated by Jackson in the 1828 election, and Clay briefly returned to his estate in Kentucky before again being elected to the Senate in 1831.

Clay was a major foe of Jackson and his administration, and unsuccessfully ran against the President in the 1832 presidential election. During the 1830s, anti-Jackson forces coalesced into the Whig Party, and Clay emerged as their natural leader. The party favored congressional supremacy and economic protectionism and saw two of its candidates, William Henry Harrison and Zachary Taylor, elected President. In 1842, Clay left the Senate to focus on another bid for the presidency. In the 1844 presidential elections, Clay faced James K. Polk and was defeated in a highly contested election. The primary issue of the campaign was slavery and the annexation of Texas, which Polk strongly favored. Clay opposed annexation, but his inconsistent answers on the question hurt him in the general election. Polk won the electoral vote 170 to 105, but beat Clay in the popular vote by a mere 38,000 votes. Clay sought the Whig nomination again in 1848 but was unsuccessful.

After his defeat, Clay returned to in private life until he went back to the Senate yet again in 1849. During his final tenure there, he helped broker the Compromise of 1850, which addressed the issue of allowing slavery in new states and delayed movements towards southern secession. Clay's work on this and earlier efforts in crafting the Missouri Compromise of 1820 earned him the enduring title of "The Great Compromiser."Henry Clay died of tuberculosis on June 29, 1852. He was the first American to lie in state at the Capital Rotunda. In 1957, a Senate Committee headed by John F. Kennedy named him one of the five best Senators ever to serve. In 1986, a panel of one hundred U.S. historians named him the best Senator in U.S. history. He is buried in Lexington, Kentucky.