Secondary AML (s-AML) encompasses a distinct subgroup of AML with either therapy-related AML or AML arising from preexisting myeloid neoplasms. Despite recent advances in the treatment armamentarium of AML, outcomes remain poor in s-AML. The purpose of this review is to highlight distinct characteristics, prognostic factors, and treatment options for patients with s-AML. Further, we focus on a distinctly poor-risk subgroup of s-AML with previous exposure to hypomethylating agents (HMAs) and describe ongoing clinical trials in this patient population. CPX-351 (liposomal daunorubicin and cytarabine) is the first drug approved for s-AML and represents an advancement in the management of fit patients with this subtype of AML. Despite incremental improvement in remission rates and survival, long-term survival remains poor. Patients who have received prior HMAs for antecedent MDS rarely benefit from CPX-351 or other cytotoxic chemotherapy regimens. The approval of venetoclax in combination with azacitidine has led to a paradigm shift in the management of newly diagnosed older unfit AML patients; however, patients with s-AML and prior HMA therapy were excluded from the landmark randomized phase 3 study. Several early phase clinical trials with both low- and high-intensity therapies are ongoing for s-AML patients, though prior HMA exposure limits inclusion in many of these studies that include HMAs. Patients with s-AML previously treated with an HMA have dismal outcomes with standard therapeutic options and are under-represented in clinical trials. Trials investigating novel therapeutic options in this population are critically needed.