The interaction of antigen with lymphocyte antigen receptors can result in either clonal expansion or unresponsiveness (anergy). In 1970, Bretscher and Cohn proposed a two-signal model of lymphocyte activation to explain this paradox: antigen receptor occupancy alone could induce unresponsiveness whereas antigen receptor occupancy plus a costimulatory signal could induce immunity. Here, Marc Jenkins reviews in vitro and in vivo manifestations of clonal anergy and evaluates the ability of the two-signal model to explain these phenomena.