Rejection of fully MHC-mismatched allografts entails the direct recognition of donor MHC molecules (direct antigen presentation) and the activation of an unusually large mass of alloreactive T cells. There is compelling evidence that apoptotic cell death of activated T cells is a critical initial step in the induction of peripheral allograft tolerance with regimens that are not inherently lymphoablative and that therapies that block T cell activation and T cell apoptosis also block the acquisition of tolerance. Thus, T cell apoptosis may play an important role in reducing the size of cytopathic T cell clones and this process may also promote the development and expansion of immune regulatory cells that are essential in the maintenance of allograft tolerance.