The main issue that rose to the fore of pre-Civil War American politics as a result of westward expansion was the possibility of the annexation of Texas. After the hero of the War of 1812, William Henry Harrison, died one month into office, John Tyler became president in 1841. Tyler hoped to build a national following through support for his foreign policy. In 1842, Tyler's secretary of state, Daniel Webster, negotiated a treaty with Great Britain settling a long dispute over the boundary between Maine and Canada, to great public approval. Tyler then moved on to the issue of annexation. Despite rampant differences of opinion between the North and South, in 1843 Tyler began a propaganda campaign in favor of the annexation of Texas. Tyler claimed that he had evidence that the British intended to seize the unstable territory from Mexico if the US did not act quickly. In efforts to garner support for annexation in the South, he played upon fears that should the British control Texas, they would outlaw slavery, sending cotton farmers back to southern states, and hurting the southern economy.

Tyler and his new secretary of state, John Calhoun secretly presented a treaty to the Senate in early 1844 that provided for the annexation of Texas. The treaty was defeated 35 to 16 in the Senate by those who sought to avoid sectional conflict over the future of slavery in the West. However, the issue of annexation dominated the election of 1844. James K. Polk ran as a Democrat, and Henry Clay ran as a Whig. Polk advocated immediate annexation of Texas, thus gaining the support of the pro-annexation South. To accommodate wary northerners, Polk adjusted his economic policy stance, and also convinced many that the addition of Texas as a slave state would serve their interests by allowing the slaveholding South to expand westward rather than pressing up against the border between North and South and thus instigating conflict. Clay and the Whigs wavered on the issue of annexation, and never established a clear platform. Polk won the presidency, victorious by only 1.5 percent of the popular vote. While this was no mandate for annexation, Polk and his cabinet quickly mobilized in efforts to bring the nation behind the goal of annexation.

Aside from Texas, Polk was faced with the issue of Oregon. He proposed that the British and Americans divide the territory at the 49th parallel. The British had long desired a split, but had suggested the Columbia River, far south of the 49th, as the point of division. Though the US had far more settlements in Oregon, the British claimed that discovery and exploration made it theirs. In 1846, Polk and Congress notified the British that they had terminated joint occupation of the territory, and that Britain could either go to war over all of Oregon or negotiate a division. Britain chose the latter, and the division was set at the 49th parallel.

Just as the issue of annexing Oregon was being quietly settled, the issue of annexing Texas flared up. In February 1845, both houses of Congress voted to annex Texas. The Mexican government, for its part, had never officially recognized Texan independence, and declared that it would consider any agreement to join the US an open act of war. Reassured by American agents, a Texas convention voted to accept annexation despite Mexico's warnings, and was admitted to the US as a state in December 1845. In anticipation of conflict, Polk ordered troops under Zachary Taylor to the border of the disputed territory.

The issue of annexation was tied tightly to the issue of slavery. Northerners feared that the annexation of Texas was part of a Southern conspiracy to extend American territory southward into Mexico and South America, thereby creating unlimited new slave states, while the north would be unable to expand similarly due to the presence of British forces in Canada. Southerners saw annexation as a way to expand the nation's cotton producing region and as a means to gain an additional two slave state votes in the Senate. Once in office, Tyler and Calhoun did not disguise their appeals to the South for support for annexation. Calhoun used reports that the British might pressure Mexico to recognize the independence of Texas in return for abolishing slavery there to construct theories about how the British might use Texas and abolition as a way to destroy the rice, sugar, and cotton growing industries in the US and gain monopolies in all three. Accompanying the treaty Calhoun and Tyler submitted to Congress was a letter from Calhoun explaining that slavery was beneficial to blacks who otherwise would fall into "vice and pauperism." The political designs underlying these strategies were clear: use southern support to move annexation forward. However, the North and wary southern congressmen held out for a more organized, practical approach to annexation, which Polk provided.

As relations between Mexico and the United States soured, the issue of Texas drove the two nations toward conflict. Mexico still hoped to regain control of Texas, or at least keep it free from American control. Once the Americans controlled Texas, Mexicans shared the fears of the American North that the United States would seize other Mexican provinces and perhaps even Mexico itself. The Mexicans feared that if this happened, they would be treated much like southern slaves. Unfortunately for Mexico, Polk's election roused enthusiasm for annexation beyond any previous level.

Polk's election, and support for his expansionist actions while in office, exemplified the growing belief that America's destiny was to expand through Texas and all the way to the Pacific Ocean. In 1845, John L. O'Sullivan, a New York journalist, gave a name to this belief. He wrote of "our manifest Destiny to overspread and to possess the whole of our continent which Providence has given us for the development of the great experiment of liberty." Proponents of Manifest Destiny often used such lofty language and often invoked God and Nature to support expansion. Many Northern Whigs at first dismissed Manifest Destiny as a cover for those who desired the expansion of slavery. However, most of those who expounded on the destiny of expansion were neither explicitly for nor against slavery. More important to them was the prospect of opening the Pacific Ocean to trade, and preserving the agricultural nature of the US. Most expansionists associated the industrialization accompanying early expansion with social stratification and class struggle. The Democrats also saw support for their political ideology in Manifest Destiny. Where tariffs and banks would tend to support the factory system, expansion would provide farmers with land and access to distant markets. As Americans continued to become farmers, Democrats believed, the democratic foundations of the Union would be preserved. Expansionists trusted that the technology of telegraphs and the railroad would continue to make distance less and less of a concern, and encouraged all out expansion into the lands of the West by settlement and annexation.