Activated T cells orchestrate the immune response that results in graft rejection; therefore, a common goal among current immunosuppressive therapies is to block T-cell activation, proliferation and function. Current immunosuppressive regimens that inhibit T cells and immune cells have greatly reduced the incidence of acute rejection following solid-organ transplant. However, the expected improvements in long-term outcomes have not been realized. This may be related to the non-immune side effects of current maintenance immunosuppressants, which target ubiquitously expressed molecules. The focus in transplantation research is shifting in search of maintenance immunosuppressive regimens that might offer improved long-term outcomes by providing efficacy in prevention of acute rejection combined with reduced toxicities. An emerging therapeutic strategy involves an immunoselective maintenance immunosuppressant that inhibits full T-cell activation by blocking the interaction between costimulatory receptor–ligand pairs. This review describes costimulatory pathways and the development of molecules, which inhibit them in the context of transplantation research. Recent clinical data using the selective costimulation blocker, belatacept (LEA29Y), as a part of a CNI-free maintenance immunosuppressive regimen in renal transplantation is highlighted.