Profiles in Courage examines eight US senators who took politically costly positions on major public questions. Its subjects include John Quincy Adams, Daniel Webster, Thomas Hart Benton, Sam Houston, Edmund G. Ross, Lucius Q. C. Lamar, George Norris and Robert A. Taft. Kennedy presents each case as an example of the pressures elected representatives face when personal conviction conflicts with party loyalty, public opinion or political ambition.

The book also considers the nature of political courage more broadly. Kennedy argues that democratic government requires compromise, but that there are moments when representatives must accept personal or electoral consequences for decisions they judge necessary. The studies range across different periods of American history, including disputes over slavery, Reconstruction, monetary policy and foreign affairs. Rather than presenting courage as simple defiance, the book explores the difficult balance between conscience, constituency, party and national interest in representative government.