T-cell costimulation is critical for all T-cell-mediated immune responses that are responsible for endpoints such as allograft rejection or autoimmune disease. Recent experimental data elucidate specific pathways for T-cell activation and negative regulatory mechanisms via unique costimulatory molecules. These data have implications for the development of novel therapeutic strategies to prevent graft rejection and improve long-term graft survival in transplant patients, and to treat autoimmune diseases in humans.