Early attempts to perform successful allogeneic hematopoietic stem cell transplants were plagued by graft rejection and graft-versus-host disease, leading many investigators to lose hope that bone marrow transplantation could ever become a useful therapeutic approach in clinical medicine. Although many subsequent discoveries contributed to the successful transformation of this area of research into lifesaving therapy, there can be no doubt that the discovery of cyclosporine (CsA) constituted one of the major advances. Even today, more than 25 years after the first description of its use in humans, CsA remains one of the cornerstones of therapy for the majority of patients undergoing allogeneic hematopoietic cell transplantation (HCT). In this review we will recount the events that have established CsA as a foundation of HCT.