Clinical solid organ transplantation became a reality with the serendipitous recognition that use of an isograft from a genetically identical living donor circumvented immunological responses. However, the ability to utilize solid organ transplants as therapy for large numbers of patients with end-organ failure is a direct consequence of the development of pharmacological immunosuppression. The Nobel Prizes awarded to Hitchings and Elion, Medawar, Murray, and Dausset bear witness to the interplay of surgical skill, immunological understanding, and bold therapeutics that still resides at the core of clinical transplantation. To the newly initiated struggling to understand the whys and wherefores of current immunosuppression, lessons learned in the past help simplify the process. Furthermore, future therapies are likely to evolve from equally important experience acquired in the present. This chapter focuses on current practice, as informed by past experiences and as a basis for understanding newer therapeutics on the horizon.