Ocurring during the presidential administration of Democrat James K. Polk, the Mexican War started in May 1846 over a dispute as to whether the Nueces or the Rio Grande River marked the boundary between Mexico and Texas, which had been admitted to statehood the preceding December. To bolster Texas's claim to the Rio Grande, Polk had ordered a small detachment of troops commanded by Zachary Taylor to the northern bank of the Rio Grande. When Mexicans attacked those troops for invading Mexican soil, Polk asserted that Mexico had declared war against the United States and won the assent of Congress, which his party controlled, to that interpretation.

Although the Whigs, including Abraham Lincoln during his single term in Congress, long denounced Polk for intentionally provoking the war and the war itself as an immoral aggression against a weaker foe in order to seize Mexican land, the two military commanders who led the war's major campaigns would later be Whig presidential candidates. One was Taylor who defeated the Mexicans in a series of battles in northern Mexico in 1846 and early 1847, most famously at Buena Vista in February 1847. The other was Winfield Scott, who, after landing a different American army at Vera Cruz in the spring of 1847, marched overland and captured Mexico city in September of that year. A treaty ending the war was signed at Guadelupe-Hidalgo outside Mexico City in February 1848 and ratified by the Senate on March 10,1848.

The treaty ceded to the United States for a payment of $15 millon all Mexican lands between the 32nd and 42nd parallels and the Pacific Ocean and Rocky Mountains, a vast area that encompasses the modem states of California, Nevada, Utah, Arizona, New Mexico, and part of Colorado. The Mexican Cession also fueled a ferocious sectional dispute about whether slavery would be allowed to exist in or be prohibited from any territory to be extracted from Mexico. That dispute began with the introduction of the Wilmot Proviso into Congress in August 1846, twenty months before any land was actually acquired, and it would not be settled until passage of the Compromise of 1850 four years later.