The diagnosis of therapy-related myeloid leukemia (t-MDS/t-AML) identifies a group of high-risk patients with multiple and varied poor prognostic features. These neoplasms are thought to be the direct consequence of mutational events induced by cytotoxic therapy. Their outcomes have historically been poor compared with those of people who develop acute myeloid leukemia (AML) de novo. The question arises whether a diagnosis of t-AML per se indicates a poor prognosis, or whether their bad outcomes result from other clinical and biologic characteristics. Because of lingering damage from prior cytotoxic therapy and, in some cases, the persistence of their primary disorder, patients with t-AML are often poor candidates for intensive AML therapy. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is higher in t-AML. Survival varies according to cytogenetic risk group, with better outcomes observed in patients with t-AML with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. Patients with t-AML should be enrolled on front-line chemotherapy trials, appropriate for de novo AML patients with similar disease characteristics. Allogeneic hematopoietic cell transplantation can cure some patients with t-AML. Most important , the molecular and genetic differences that appear to determine the phenotype and the outcome of these patients need to be investigated further.