Activation of self-reactive T cells that specifically destroy the pancreatic β-cells is one of the hallmarks in the development of type 1 diabetes. Thus, for prevention and treatment of this autoimmune disease, approaches to induce and maintain T cell tolerance toward the β-cells, especially in islet transplantation, have been actively pursued. Noticeably, many of the recent protocols for inducing transplant tolerance involve blockade of positive T cell costimulation extrinsically. Though highly effective in prolonging graft survival, these strategies alone might not be universally sufficient to achieve true tolerance. As the mystery of the suppressive and regulatory T cells unfolds, it is becoming appreciated that exploiting the intrinsic molecular and cellular mechanisms that turn off an immune response would perhaps facilitate the current protocols in establishing T cell tolerance. In this perspective, here we summarize the recent findings on the negative costimulation pathways, in particular, the newly identified PD-1 : PD-L interactions. On the basis of these observations, we propose a new principle of curtailing pathogenic T cell response in which blockade of positive T cell costimulation is reinforced by concurrent engagement of the negative costimulation machinery. Such a strategy may hold greater hope for therapeutic intervention of transplant rejection and autoimmune diseases. Copyright © 2003 John Wiley & Sons, Ltd.