High-dose cyclophosphamide was developed as a conditioning regimen for allogeneic bone marrow transplantation. Later, it was discovered that high-dose cyclophosphamide spares early hematopoietic stem cells because of their relatively high levels of the enzyme aldehyde dehydrogenase; thus, high-dose cyclophosphamide is a potent immunosuppressive agent, but nonmyeloablative. Recent reports demonstrate that high-dose cyclophosphamide without bone marrow transplantation induces durable treatment-free remissions in severe aplastic anemia and a variety of other autoimmune disorders; however, there is lingering concern about the safety of this approach.