In December 1842 Breese won election to the U.S. Senate and promptly resigned from the bench. During his single term from 1843 to 1849, he loyally supported most major Democratic policies: a low tariff, a tough stance against England in the longstanding dispute over the Oregon boundary, the annexation of Texas, and the Mexican War. Although in principle he opposed federal grants of public lands to aid internal improvements within the states, he made an exception for railroad and canal projects, especially those that promised to benefit the state of Illinois.

In 1852 Koerner was elected lieutenant governor of Illinois on the Democratic ticket, serving from January 1853 to January 1857. When Illinois's powerful Democratic senator Stephen A. Douglas introduced the Kansas-Nebraska Act in 1854, which repealed the previous prohibition on slavery in some of the western territories, Koerner was strongly opposed to the measure but hesitated to voice public opposition while still a member of the Democratic state administration. For two years he hoped in vain to turn away the Democratic party from support of Douglas's measure.

In the 1840s Lovejoy became an active political abolitionist, running unsuccessfully for Congress as a Liberty party candidate in 1846. In August 1848 he attended the Free Soil convention in Buffalo and again ran unsuccessfully as that party's candidate for Congress from Illinois's Fourth District.

Throughout his six years in Congress, Bissell championed liberal land policies such as homesteads, bounties to veterans, and grants to railroads. Although in 1850 he favored the Fugitive Slave Act and other compromise measures, in 1854 he broke with his party's leadership and refused to support the Kansas-Nebraska Bill because it repealed the Missouri Compromise. In May 1854 he was incapacitated by an illness of some years' standing, probably secondary syphilis affecting the sacrum. While acutely ill, he converted secretly to his wife's Roman Catholic faith.

From 1857 to 1859 Bagby resided in Washington, where he served as correspondent for a number of southern newspapers. During this period, in 1858, he sent the first of eight "Mozis Addums" letters to the Southern Literary Messenger in Richmond. The letters are modeled on the speech of backwoods characters Bagby had known as a youth in southside Virginia and are influenced by the well-established tradition of southwest dialect humor.