Antibody-mediated rejection (AMR) has been identified among the most important factors limiting long-term outcome in cardiac and renal transplantation. Therapeutic management remains challenging and the development of effective treatment modalities is hampered by insufficient understanding of the underlying pathophysiology. However, recent findings indicate that in addition to AMR-triggered activation of the classical complement pathway, antibody-dependent cellular cytotoxicity by innate immune cell subsets also promotes vascular graft injury. This review summarizes the accumulating evidence for the contribution of natural killer cells, the key mediators of antibody-dependent cellular cytotoxicity, to human AMR in allotransplantation and xenotransplantation and illustrates the current mechanistic conceptions drawn from animal models.