The first large-scale argument over slavery erupted in 1819 when Missouri petitioned for admittance into the Union. Many of the settlers in Missouri were slave owners who had migrated from the South with their slaves. These people wanted slavery to be an accepted part of the new state constitution. Other residents of the territory did not want slavery approved. More significantly, however, the politicians of the North and the South feared the admission of the new state because it would upset the balance of power in the Senate. Until this point, the struggle for power in the Senate had been tempered by the orderly admission of free and slave states to the Union. Earlier in 1819, the Union had been comprised of eleven free states and eleven slave states. Before Missouri petitioned for admittance into the Union, Alabama had been admitted as a slave state. If Missouri was admitted as another slave state, the balance of power would be lost. The controversy over Missouri gained momentum when Representative James Tallmadge of New York proposed that "the further introduction of slavery" into the new state be forbidden and that the children of slaves presently living in the state be free when they reach twenty-five years of age. Because membership in the House of Representatives is based on population, and the North was the most populated region, the Tallmadge Amendment was passed and sent to the Senate. The amendment was finally defeated in the Senate after a long and forceful debate. The passage of the Tallmadge Amendment in the House crystallized in the minds of Southern senators the necessity of preserving the balance of power in the Senate. If the South could preserve this balance, it could block legislation passed by the Northern-dominated House that would in any way be detrimental to the welfare of the Southern states.

The impasse was resolved when Maine separated from Massachusetts and applied for statehood. A compromise, supported by Henry Clay, was proposed and accepted by both sides. This compromise, known as the Missouri Compromise, provided for the admittance of Missouri as a slave state and the admittance of Maine as a free state, thereby preserving the balance of power. In addition, the North was able to hold its position that Congress should determine the expansion of slavery into the territories by including a provision that forbade slavery forever in the Louisiana Purchase north of the 36°30' parallel.