Relapsed acute myeloid leukemia (AML) after an allogeneic hematopoietic cell transplant (allo-HCT) entails a poor prognosis. Treating these cases is challenging due to lack of effective therapies and, in some cases, poor performance status and/or presence of graft-versus-host disease (GVHD), among others. No randomized controlled trial (RCT) has ever been conducted comparing a second allo-HCT against other treatments. Existing data are mainly from observational studies or registries. Success of a second allo-HCT is dependent on appropriately selecting patients who might achieve best outcomes with reasonable non-relapse mortality (NRM) risk. Several factors are associated with worse outcomes, namely a shorter time from first allo-HCT to relapse or to the second allo-HCT, and AML not being in complete hematologic remission (CR). Patients relapsing earlier than 6 months or having active/persistent disease should be enrolled in clinical trials. Limitations of the published literature include retrospective small size studies, a heterogeneous population, and absence of information on somatic mutations, among others. Future studies assessing the role of a second allo-HCT should evaluate the impact of IDH1, IDH2, or others on outcomes; and the feasibility and efficacy of targeted therapies in the pre-, peri-, or post-second allo-HCT setting.