BACKGROUND: Current maintenance immunosuppression agents have been critical to the improved graft and patient survival rates in solid organ transplantation observed over the past decade. However, long-term follow-up has revealed that these agents are associated with troublesome side effects and chronic toxicity, contributing to graft loss and death. OBJECTIVES: Costimulation blockade has long been recognized as an important target for immunomodulation in solid organ transplantation. Belatacept, a high-affinity chimeric fusion protein that binds to CD80/CD86 on antigen-presenting cells, has shown great promise in renal transplantation and is now in Phase III trials. METHODS: This review explores the development and efficacy of belatacept, compared with currently approved immunosuppressive agents used in transplantation. RESULTS: Belatacept seems to be an effective alternative to current maintenance immunosuppressive therapies, with no apparent end organ toxicity and a minimal side-effect profile. This agent works best when used in combination with therapies that target different pathways of T-cell activation, but the optimal regimen has not yet been identified. Data generated in ongoing clinical trials will be essential in validating previous studies and for further development of belatacept-based combinatorial strategies.