Heart transplantation has been performed clinically for four decades, and has become the standard of care for end-stage heart disease. Our understanding of the immunobiology of transplantation has made tremendous strides, but our knowledge still lags behind the clinical use. As a result, nonspecific immunosuppression remains the standard therapy. This chapter is a review of our present knowledge of the immunobiology of allotransplantation and xenotransplantation with emphasis on antigen presentation, costimulation, and T-cell activation in the context of transplantation. The molecular events of T-cell activation, with some emphasis on the sites of action of present day immunosuppression, are reviewed. Basic aspects of immunosuppression are reviewed elsewhere in this edition. Given the paucity of allografts, xenografts are being considered as an alternative donor source. This being the case, cellular and humoral response to xenografts is considered and contrasted with our understanding of allograft immunity. Basic mechanisms of tolerance are discussed, with examples of experimental tolerance induction in small and large animals. A brief description of special considerations for the immunology in human neonate/infant recipients is mentioned. Understanding the immunobiology of transplantation is key to making decisions regarding heart transplant recipients today, in addition to developing better protocols and the induction of tolerance in the future.