He naturally opposed the Kansas Nebraska Bill of 1854, which repealed the Missouri Compromise and established the principle of popular sovereignty in the Territories.
The acquisition of Louisiana in 1803, which gave a new field for the growth of the slave power, though not made in its interest, the Missouri Compromise (1820), the annexation of Texas (1845), the Fugitive Slave Law (1850), the Kansas-Nebraska bill (1854), the Dred Scott decision (1857), the attempts to acquire Cuba (especially in 1854) and to reopen the foreign slave trade (1859-1860), were the principal steps - only some of them successful - in its career of aggression.
In the Missouri Compromise debates he supported the anti-slavery programme in the main, but for constitutional reasons voted against the second clause of the Tallmadge Amendment providing that all slaves born in the state after its admission into the Union should be free at the age of twenty-five years.
The sequel was the repeal of the Missouri Compromise in the Kansas-Nebraska Bill of 1854.
A Republican in politics, and a firm believer in the doctrines of strict construction and state sovereignty which Thomas Jefferson had been principally instrumental in formulating, he opposed consistently the demand for internal improvements and increased tariff duties, and declined to follow Henry Clay in the proposed recognition of the independence of the Spanish colonies in South America and in the Missouri Compromise legislation.