Therapy-related leukemia (myelodysplasia and acute myeloid leukemia-t-MDS/AML) is a well-known complication of conventional chemoradiotherapy used to treat a variety of primary malignancies including Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), sarcoma, and ovarian and testicular cancers. The median time to development of t-MDS/AML is 3-5 years, with the risk decreasing markedly after the first decade. t-MDS/AML is the major cause of non-relapse mortality after autologous hematopoietic cell transplantation (HCT) for HL or NHL. The magnitude of risk of t-MDS/AML is higher, and the latency is shorter after HCT, compared to conventional therapy. Two types of t-MDS/AML are recognized depending on the causative therapeutic exposure: an alkylating agent/radiation-related type and a topoisomerase II inhibitor-related type. Inter-individual variability in the risk for development of t-MDS/AML suggests a role for genetic variation in susceptibility to genotoxic exposures. Treatment of t-MDS/AML with conventional therapy is associated with a uniformly poor prognosis, with a median survival of 6 months. Because of the poor response to conventional chemotherapy, allogeneic HCT is recommended. Current research is focused on developing risk prediction and risk reduction strategies.