A moderate on the slavery issue, in 1850 he twice opposed the radicals at the Nashville Convention and supported the Compromise of 1850. In 1852 he vainly sought the Democratic nomination for the vice presidency. He failed in 1856 in a second bid for nomination for the vice presidency, and in 1857 he lost out in a campaign for the Senate.
Except in politics, the 1850s were good years for Pillow, as he expanded his agricultural and political interests into Arkansas and abandoned his law practice. By 1860 he was a very wealthy planter, owning large numbers of slaves and plantations in both Arkansas and Middle Tennessee. He continued to call "Clifton Place," his Maury County plantation, home.
In 1860 Pillow was a Stephen Douglas Democrat, opposed to precipitate action on the part of the South. Following the election, however, Pillow cast his lot with Governor Isham Harris and the Confederacy. In April 1861, two months before Tennessee left the Union, Pillow traveled to Montgomery, Alabama, to vainly offer his services to Jefferson Davis. On 9 May, three days after the general assembly authorized the creation of a Provisional Army of Tennessee, Governor Harris named Pillow to its command with the rank of major general. He accepted the challenge with enthusiasm, arming, accoutering, and organizing into an army the thousands of eager volunteers assembled at Memphis and other camps of instruction.