The history of immunosuppression in renal transplantation and trends that might inform its future are discussed. A philosophical paradigm shift away from additive to reductive immunosuppressive protocols is announced. Newer immunosuppressive strategies that use the deeper understanding of the immunobiology of organ transplantation is detailed, with particular reference to inhibition of costimulatory pathways and blockade of antigen-specific signaling, as well as to the potential for tolerance development. Agents that might use novel immunosuppressive pathways are discussed. The future of transplantation immunosuppression is bounded only by our imagination and our understanding of the basic science of the field.