The Kansas-Nebraska Act, which was signed into law in May 1854, reignited the sectional conflict over slavery extension that many people believed had been settled permanently by the Compromise of 1850. Framed by Illinois' Democratic Senator Stephen A. Douglas and endorsed as a Democratic party measure by President Franklin Pierce, this legislation organized the entire remaining unorganized area of the Louisiana Territory from the 36° 30' line in the south to the Canadian border into two new territories, Kansas, west of Missouri, and Nebraska, west of Iowa and Minnesota Territory. Douglas introduced the bill primarily to encourage settlement in, and the construction of a railroad line to the Pacific coast across, that area, for no land could be legally sold or land grants given to railroads until it was formally organized. But what made the measure so controversial was its implications regarding slavery expansion.

According to the Missouri Compromise of 1820, slavery was to be "forever prohibited" from that part of the Louisiana Territory north of the 36° 30' line, and southern democrats refused to allow the bill to pass if that prohibition stood. Although some Southerners demanded an explicit repeal of the 1820 line, Douglas's measure did so indirectly by asserting that it was now "inoperative and void" because it had been "superseded" by the popular sovereignty provisions of the Compromise of 1850 that now also applied to Kansas and Nebraska, not just New Mexico and Utah. Indeed, the language of the act was even more explicit than the earlier legislation had been that it was the residents of the territories themselves who would make the decision on slavery.

By opening up an area from which slavery had been barred for thirty-four years to the possible extension of slavery, the Kansas-Nebraska Act outraged many Northerners, including Abraham Lincoln who reentered political life because of his fury at the bill. All northern Whigs and Free Soilers in Congress and half the northern Democrats in the House voted against it, but most southern Whigs in both chambers voted for it after Free Soilers denounced it as an intolerable act of aggression by the Slave Power against freedom and the North.

The Kansas-Nebraska Act is arguably the most consequential piece of legislation ever enacted by Congress. It ignited four years of turmoil between northern and southern settlers in Kansas that made "Bleeding Kansas" an issue in the 1856 election and disrupted the Democratic party during James Buchanan's subsequent presidential administration. It split the Whig party permanently along North/South lines. It helped start a massive voter realignment against the Democrats in the North in the elections of 1854 and 1855 from which the Democratic party would not recover until the congressional elections of 1874. And reaction against it launched the Republican party in 1854, an exclusively northern and overtly antisouthem, anti-slavery-extension party that would elect Lincoln president in 1860, thereby provoking southern secession and the Civil War.