The first and most important theme of Profiles in Courage is the concept of "political courage.”Although Kennedy borrows from the lives and careers of the senators described in this book, his own idea of political courage is highly complex and peculiar. It reflects the vagaries and ambiguity of political life, and the unique history and problems of American political history. As Profiles in Courage argues and demonstrates, the nature of political courage is not defined by a generic style of action or model of decision-making, but, as Kennedy argues, remains radically dependent upon the needs of a specific situation.

Kennedy's opening images of political courage are shown through their detractors. The Federalists, who describe their fellow Federalist John Quincy Adams as "selfish" and as "Lucifer," give some indication to the highly personal character of Adams’s idea of political courage. Adams's opponents deride his commitment to his personal ideals over the perceived needs of the Federalist party and see these ideals as an intrusion of selfishness into his duties as a representative of a specific constituency. Through Adams, Kennedy rebuts this view, arguing that the higher duty of a senator is to aid in the creation and enactment of sound policy, policy that protects not just one man, or a state, or a region, and instead puts the nation first.