The Kansas–Nebraska Act was passed in May 1854 and ultimately defined the Pierce presidency. The political turmoil that followed the passage saw the short-term rise of the nativist and anti-Catholic American Party, often called the Know Nothings, and the founding of the Republican Party.[126][127][128]

Northerners resented Pierce's attempted expansion of slavery through Kansas–Nebraska and Cuba.[131][132] In this 1856 cartoon, a Free Soiler is held down by Pierce, Buchanan, and Cass while Douglas shoves "Slavery" (depicted as a black man) down his throat.
Even as the act was being debated, settlers on both sides of the slavery issue poured into the territories so as to secure the outcome they wanted in the voting. The passage of the act resulted in so much violence between groups that the territory became known as Bleeding Kansas. Thousands of pro-slavery Border Ruffians came across from Missouri to vote in the territorial elections although they were not resident in Kansas, giving that element the victory. Pierce supported the outcome despite the irregularities. When Free-Staters set up a shadow government, and drafted the Topeka Constitution, Pierce called their work an act of rebellion. 