The sectional debate over the expansion of slavery into the Western territories played the largest role in killing the Whig Party. Following the Compromise of 1850, it appeared to many that the slavery issue had been settled and that the Democratic principle of popular sovereignty would determine the status of slavery's legality on a local basis in newly acquired states in the West. By 1854, this principle had become seriously challenged by civil violence in places like Kansas and Nebraska between pro-slavery and anti-slavery settlers. How could popular sovereignty work if the settlers couldn't agree on so much as a unified territorial capital or how to draft a constitution and vote for its passage? The Whig Party did not have a coherent position on slavery in the West, with its Northern voting base being anti-slavery and its Southern base being pro-slavery. Northern Whigs virulently opposed the repeal of the longstanding Missouri Compromise and the Kansas Nebraska Act while Southern Whigs supported. The party began hemorrhaging huge amounts of voting support due to the sectional divide, to Republicans as well as Know Nothings in the House. One remarkable example of this political shift was embodied in Millard Fillmore, the last Whig president, running for President again as the Know Nothing candidate in 1856 and carrying the state of Maryland. The reinsertion of slavery into the national conversation due to the Kansas crisis killed the Whigs, with most prominent Northern Whig politicians such as Abraham Lincoln and William Seward joining the new Republican Party that had a unified anti slavery stance. Southern Whigs either became Democrats or matriculated into small regional opposition parties.

There are a few points in American history where third party populism sprang up into competitiveness on the national level following the Civil War. The Greenback Party in the decades after the civil war was probably the first prominent example, along with the Populists at the end of the 19th century, the Progressive Party(ies) of the early to mid 20th century, etc.