Immunosuppression after heart transplantation has significantly reduced the incidence of rejection and improved patient outcomes. However, long-term graft outcome is challenged by multiple factors, including the effects of the immunosuppressive drugs used and the chronic rejection process. A better understanding of the multiple mechanistic processes involved may provide evidence of the feasibility of the best approach to achieve the ultimate goal of donor-specific tolerance. This chapter will summarize the role of the immune systems in transplantation, focusing on the interaction between innate and adaptive immunity, Human Leukocyte Antigens (HLA) polymorphism and nomenclature, and outlines the pathways of alloantigen presentation. The chapter also covers T cell-mediated rejection, antibody responses, and immunosuppressive strategies and explores the concept of tolerance.