© 2014 The Authors. There is no standard of care for older patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive therapy, and prognosis with currently recommended low-intensity therapies (decitabine, azacitidine, and low-dose cytarabine [LDAC]) remains poor. One promising strategy is to combine low-intensity treatments with novel agents. Gemtuzumab ozogamicin, tipifarnib, and barasertib have been investigated in phase 2/3 or 3 trials combined with LDAC, and phase 3 trials are currently investigating sapacitabine plus decitabine, and volasertib plus LDAC in AML. This review discusses current treatment recommendations and the development of combination therapies for older patients unfit for intensive therapy.