Arguments over the issue of slavery developed in Congress after Missouri, part of the Louisiana Purchase area, applied in 1818 for admission as a state. Representatives of Southern states objected to a proposal that would keep slavery out of Missouri. This issue was settled, temporarily, by the Missouri Compromise of 1820. Slavery was permitted in Missouri, but not in other states to be formed out of the Louisiana Purchase area north of Missouri's southern boundary.

The slavery question kept on festering, but was overshadowed for some years by other issues. During President Monroe's administrations (1817-25) there was a period, called the Era of Good Feeling, when sectionalism and political strife seemed to have disappeared. Long-standing disputes over Florida were settled when it was ceded by Spain through a treaty that was signed in 1819 and ratified in 1821. The Monroe Doctrine was proclaimed in 1823 to warn European powers against attempts to extend control over territory on the American continents.

Political harmony ended during the administration of John Quincy Adams (1825-29). Under Andrew Jackson, elected President in 1828, the modern Democratic party emerged from the old Jeffersonian Republican party. Much controversy resulted when Jackson vetoed a bill to recharter the Bank of the United States, a private institution that wielded great influence over the country's financial policy. Opposition to Jackson, who appealed to ordinary citizens even more directly than had Jefferson, brought into being the Whig party.The question of a state's right to prevent legislation hostile to its interests came up during Jackson's Presidency. In 1832 South Carolina objected to a tariff act and asserted the right to declare acts of Congress null and void. Jackson's readiness to use force to crush nullification, together with passage of a tariff act less objectionable to South Carolinians, caused the controversy to subside.