Antigen-specific T cell responses have primarily been considered in terms of activation signals delivered through the TCR and the co-stimulatory molecule CD28. In the past few years, studies have demonstrated the critical importance of inhibitory signals for regulating lymphocyte activation. CD28 and its homologue cytotoxic T lymphocyte antigen-4 (CTLA-4) share the same counter-receptors on antigen-presenting cells, but recent experiments have shown that CD28 and CTLA-4 have opposite effects on T cell activation. The mechanisms responsible for integrating these activation and inhibitory signals at the cellular and molecular levels are just beginning to be elucidated.