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This chapter outlines the events involved in the adaptive and innate immune responses to a transplant and the subsequent mechanisms of rejection, concluding with current clinical and experimental strategies to protect transplants from immune-mediated damage. The recognition of foreign antigens by naive host (recipient) T cells is a principal step in the rejection process. Allorecognition in the presence of costimulation results in the activation and expansion of T-cells that recognize the mismatched donor alloantigens. Immunosuppressive therapy can be credited with the vast improvements in transplant survival. The chapter explores the underlying mechanisms of action in relation to the immunobiology. Newer monoclonal antibodies include alemtuzumab, rituximab, basiliximab, and daclizumab, which target specific T-cell surface proteins. The advances in immunosuppression have improved short- and medium-term graft survival rates and reduced the rates of acute rejection, but this has not been followed by a comparable reduction in long-term graft dysfunction rates.