Acute myeloid leukemia (AML) secondary to antecedent hematologic disorder or prior therapeutics for cancer represent a diverse group of leukemias often associated with inferior outcomes. Conventional therapy with cytarabine-based chemotherapy has been the mainstay of care for the past 30 years with disappointing overall outcomes. Novel therapies, including liposomal cytarabine/daunorubicin, and venetoclax-based therapies have emerged as options in recent years based on studies showing improvement in outcomes over standard-of-care therapies. Despite these advances, mutations in TP53 are associated with inferior response to both therapies and represent an area of unmet clinical need. Novel strategies with immune-targeted therapies such as CD47 monoclonal antibodies appear active in early-phase studies, but randomized studies have yet to report outcomes leading to approval. Allogeneic transplant remains the only known curative therapy for many of these cases. Nonetheless, pretransplant high-risk molecular features of secondary AML are associated with inferior outcome despite transplantation. An optimal approach to secondary AML is yet to be determined.