Achieving a tolerant state specific to the transplanted graft without subjecting patients to the risks of non-specific immunosuppression is the goal of transplant immunologists. In spite of the success achieved with currently available immunosuppresive therapies over acute rejection, an ongoing T cell mediated alloimmune response still poses a major challenge to the health of an allograft through chronic rejection. Modulating these destructive alloresponses through T cell costimulation blockade is a promising area of interest. In this article, we review our current knowledge about the role of various positive and negative costimulatory pathways during an alloimmune response. The ultimate nature of that response depends on the complex interaction between these positive and negative costimulatory pathways. We discuss the progress that has been achieved so far, through targeting these individual pathways, their interaction with other costimulatory pathways and the currently available immunosuppressive agents in various organ transplant models.