Although transplantation has revolutionized care for patients with end-stage organ failure due to the development of new immunosuppressive drugs, significant problems persist with treatments designed to prevent acute graft rejection. There is a real need for improved methods to maintain allograft function by preventing immune-mediated rejection. Accumulating evidence suggests that the inhibition of T cell costimulation may promote antigen-specific tolerance of transplants. In particular, blockade of the CD28 and CD40 costimulatory pathways has shown great promise in preventing transplant rejection in rodents and nonhuman primates. This paper discusses the human immune system, costimulatory pathways, and new therapeutic agents that regulate so-called costimulatory second signaling to maintain transplant function without general suppression of the immune system.