The specific political crisis that culminated in secession and civil war stemmed from a dispute over the expansion of slavery into new territories. Under the Missouri Compromise of 1820, Congress had agreed to admit Missouri as a slave state, but bar slavery in the territory west and north of Missouri.

The acquisition of vast new lands during the Mexican War (1846–1848), however, reopened the debate. Free-state politicians such as David Wilmot, who personally had no sympathy for abolitionism, feared that unpaid slaves would provide too much competition for free labor, and thus effectively keep free-state migrants out of newly opened territories.

Slaveholders felt that any ban on slaves in the territories was a discrimination against their peculiar form of property, and would undercut the financial value of slaves, the institution itself, and their national political dominance. In Congress, the end of the Mexican War was overshadowed by a fight over the Wilmot Proviso, a provision that Wilmot tried (and failed) to enact to bar slavery from all lands acquired in the conflict.

The dispute led to open warfare in the Kansas Territory after it was organized in the Kansas-Nebraska Act of 1854. This act repealed the prohibition on slavery there under the Missouri Compromise, and put the fate of slavery in the hands of the territory's settlers, a process known as "popular sovereignty."

Proslavery Missourians expected that Kansas, due west of their state, would naturally become a slave state, and were alarmed by an organized migration of antislavery New Englanders. Soon heavily armed "border ruffians" from Missouri battled antislavery forces under John Brown, among other leaders. Hundreds were killed or wounded. Southern congressmen, perceiving a Northern conspiracy to keep slavery out of Kansas, insisted that it be admitted as a slave state. Northerners, pointing to the large and growing majority of antislavery voters there, denounced this effort. By 1860, sectional divisions had grown deep and bitter.

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