Multi-organ transplantation involves the simultaneous or sequential transplantation of more than one organ into a single recipient and may be offered to patients with end-stage organ failure affecting multiple organs due to a variety of underlying conditions. This chapter details the history and current landscape of multi-organ transplantation in the United States, discusses modern-day organ allocation policies, and provides an overview of the heart-liver, heart-kidney, and triple-organ transplantation experience. We highlight how ethical considerations regarding the just and equitable distribution of limited resources pose similar, albeit more nuanced, challenges to multi-organ transplantation as they do to single-organ transplantation and describe how careful candidate selection and ongoing refinements in surgical technique and medical management have allowed increasingly more patients, including those with irreversible, multisystem organ failure, to benefit from organ transplantation.