Entering the Senate at the same time as Charles Sumner, Wade joined a small group of antislavery senators who ceaselessly attacked the "peculiar institution" in general and the Fugitive Slave Act in particular. He gradually developed a reputation as a fearless radical who was as outspoken as he was honest, and he knew how to gain the respect of southern opponents. When threatened with a challenge, he let it be known that as a senator he would refuse to fight, but as Ben Wade he would not hesitate to do so. His pithy replies to southern taunts became famous, and, in addition to his antislavery stand, he was also active on behalf of a homestead bill and protective tariffs; however, he did not support special considerations for private corporations.
Strongly opposed to the Kansas-Nebraska Act of 1854, which opened the West to slavery, Wade joined with others to found the Republican party in Ohio. He made common cause with his radical colleagues in repelling southern attacks and continued to favor protection, homestead laws, and internal improvements. His political prominence caused him to be mentioned for the presidency in 1860.