© 2017 Elsevier Inc. All rights reserved. Allotransplantation is the most common treatment for end stage kidney, liver, lung, and heart disease. In order to accommodate the allograft, the recipient must be immune-suppressed, to prevent rejection of the graft by the innate and adaptive immune system. Acute rejection has been largely avoided through improved methods of organ procurement, surgical techniques, and immunosuppressive regimens. However, long-term immunosuppression has many drawbacks, leaving patients susceptible to nephrotoxicity, malignancies, and infection. Tolerance is the absolute goal in clinical transplantation, where a patient can be weaned from immunosuppression with no subsequent rejection; however, this is rarely achieved. Withdrawal from these therapies usually results in allograft destruction by the recipient immune system. Here, we outline current knowledge on the immune response to the allograft at the innate and adaptive levels, the impact of withdrawal from immunosuppression and subsequent allograft rejection mediated by a highly activated T cell compartment, and the role of homeostatic proliferation in this setting. Finally, we describe current investigations into novel therapies for the induction of tolerance.