The recognition by the immune system of nonself determinants on cells, tissues, or organs transplanted between genetically disparate members of the same species can lead to a potent allogeneic response that is responsible for rejection. We review here fundamental concepts that underlie the origins and biology of allorecognition in the mammalian immune system. We examine why and how T cells are alloreactive and discuss emerging evidence of allorecognition by innate immune cells. The nature of T cells (naïve vs. memory) and the alloantigen presentation pathways (direct, indirect, and semidirect) that initiate the allogeneic response are outlined.