INTRODUCTION: Acute myeloid leukemia [AML] is a heterogenous group of primary hematopoietic neoplasms arising from myeloid precursor cells. Up to 50% of patients failed to achieve remission with initial therapy and go on to develop refractory AML. Whenever possible, enrollment in a clinical trial in view of the paucity of evidence surrounding a clearly superior treatment modality is recommended, and the therapy which provides the best chance for cure post remission is allogeneic hematopoietic stem cell transplantation [HCT], with much of everyday clinical decision-making in relapsed/refractory (R/R) AML surrounding the choice of the least toxic regimen that could achieve remission and enable prompt HCT. DISCUSSION: We discuss a variety of treatment modalities employed in the R/R AML setting beginning with traditional cytotoxic regimens. We then turn our attention to targeted therapies that have shown efficacy in specific patient populations such as the IDH inhibitors and FLT3 inhibitors and lastly, we turn our attention to immunotherapeutic agents employed in the R/R in the setting, such as CD33 inhibitors and bispecific antibodies. CONCLUSION: It appears increasingly clear that approaching AML as a homogenous disease entity is unsatisfactory in view of the variations in such disease factors as cytogenetic and molecular markers, age, and disease severity at presentation; all of which contribute significantly to heterogeneity of the disease. Moving forward, treating AML would likely require tailored therapy following advances in technology such as molecular profiling, drug sensitivity and resistance testing.