This chapter focuses on current practice, as informed by past experiences and as a basis for understanding newer therapeutics on the horizon. Long-term survival of allograft in humans first occurred with the introduction of azathioprine (AZA). Early use of cyclosporine (CyA) in animals and humans as monotherapy seemed effective in preventing acute rejection crises. Mycophenolate mofetil (MMF) was a new modified preparation of an older agent that enhanced its absorption and stability. Maintenance immunosuppression is the long-term therapy required to ensure allograft survival, administered with the dual intentions of avoiding both immunological injury and drug-related toxicity. Discovery of new agents is informed by our evolving understanding of how immunological processes injure allograft, with substantial attention now being devoted to antibody-mediated injury and lymphoid tissue of B-cell lineage. It is now common to use biologics, such as polyclonal or monoclonal antibodies, for a short time as induction of acute rejection.