Prospective evidence for management of therapy-related acute myeloid leukemia (t-AML) is limited, with evidence extrapolated from major AML trials. Optimal treatment is challenging and needs consideration of patient-specific, disease-specific, and therapy-specific factors. Clinical trials are recommended, especially for unfit patients or those with unfavorable cytogenetics or mutations. CPX-351 as an upfront intensive chemotherapy is preferred for fit patients; venetoclax with decitabine or azacitidine is an option for patients unfit for intensive chemotherapy. Hematopoietic cell transplant, the only curative option, should be offered to eligible patients with intermediate or unfavorable t-AML or patients with good-risk AML with minimal residual disease. Ongoing clinical trials focusing on treatment of t-AML, including targeted agents and immunotherapy, bode well for the future., (Copyright © 2019 Elsevier Inc. All rights reserved.)