The majority of patients with acute myeloid leukemia (AML) develops refractory/relapsed (R/R) disease even in the presence of novel and targeted therapies. Given the biological complexity of the disease and differences in front-line treatments, there are only approved therapies for subgroups of R/R AML and enrollment into clinical trials should be first priority. Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative strategy for the majority of patients. Therapeutic approaches, including allogeneic HCT, triggered by the presence of measurable residual disease (MRD) have recently evolved to prevent overt hematological relapse. Salvage therapy with chemotherapy or targeted therapy is frequently given prior to HCT to reduce the leukemic burden. Gilteritinib is approved by the Food and Drug Administration (FDA) and European Medicines Agency for patients with relapsed FLT3 mutated AML, while targeted therapy for relapsed IDH1/2 mutated AML has only FDA approval. Patients who are refractory or relapse after azacitidine and venetoclax (AZA/VEN) have a dismal outcome. In this setting, even available targeted therapies have unsatisfactory results. Examples of ongoing developments include menin inhibitors, a targeted therapy for patients with mutated NPM1 or KMT2A rearrangements, antibodies targeting the macrophage immune checkpoint CD47 as well as triple combinations involving AZA/VEN. The latter cause significant myelosuppressive effects, which make it challenging to find the right schedule and dose.