Scholarly interests include nineteenth and early twentieth century American literature; modernism in the arts; African American literature; slavery and abolition; literary theory and criticism; Shakespeare.

Publications include a monograph on American literary and cultural criticism, 1900-1945, in The Cambridge History of American Literature, vol. 5 (2003). Professor Cain is a co-editor of the Norton Anthology of Literary Theory and Criticism (1st ed., 2001; 2nd ed., 2010), and, with Sylvan Barnet, he has co-authored a number of books on literature and composition. He also has co-edited a 2-volume anthology of American Literature (1st ed., 2004; 2nd edition, 2013/14).

Other recent publications include essays on Ralph Ellison, Ernest Hemingway, George Orwell, Shakespeare, Edith Wharton, Willa Cather, and the painter Mark Rothko.