Relapsed/Refractory acute myeloid leukemia (RR AML) is difficult to treat and associated with poor outcomes. Patient and disease features, such as age, cytogenetics, duration of remission and receipt of prior allogeneic hematopoietic cell transplant (allo-HCT) can distinguish prognostic groups within this heterogeneous patient population. Overall, the goal of treatment for RR AML is to achieve complete remission with salvage therapy and, if possible, proceed to potentially curative allo-HCT. Classically, the treatment of RR AML patients has focused on high intensity salvage chemotherapy regimens, including repeating the initial successful induction regimen, in younger and fit patients, low intensity therapy regimens in older and unfit patients, and clinical trials when available. Examples of salvage regimens include FLAG -/+ idarubicin, HiDAC, MEC, cladribine-based regimens, clofarabine-based regimens, LDAC and hypomethylating agents. The emergence of new agents, such as the Bcl-2 inhibitor, venetoclax, as well as targeted therapies including FLT3 inhibitors, IDH1 inhibitors, and IDH2 inhibitors, has challenged the RR AML treatment paradigm. A number of other novel drugs and immune approaches are in various stages of development for the treatment of RR AML, providing hope for a future with improved outcomes for patients with RR AML.