Tolerance induction to alloantigens is a major challenge in transplant immunology. Whereas conventional immunosuppression inhibits the immune system in a nonspecific way, thereby also undermining an appropriate immune response towards potentially harmful infectious organisms, tolerance in a transplantation setting is restricted to alloantigens, while protective immunity is preserved. Moreover, tolerance implies an immunological status that is preserved after withdrawal of the tolerance-inducing therapy. Among the most promising strategies to induce immunological tolerance are costimulation blockade and establishment of mixed chimerism. Despite significant advances, we still know little about the mechanisms responsible for such tolerance. In this article, we discuss tolerance induction to transplantation antigens by costimulation blockade.