Posttransplant relapse is the most significant challenge in allogeneic stem cell transplantation (alloSCT). Posttransplant interventions, in conjunction with optimal conditioning regimens and donor selection, are increasingly supported by evidence for their potential to prolong patient survival by promoting antileukemia or graft-versus-leukemia effects. Our review begins by highlighting the current evidence supporting maintenance therapy for relapse prevention in acute myeloid leukemia and acute lymphocytic leukemia. This includes a broad spectrum of strategies, such as targeted therapies, hypomethylating agents, venetoclax, and immunotherapies. We then shift our focus to the role of disease monitoring after alloSCT, emphasizing the potential importance of early detection of measurable residual disease and a drop in donor chimerism. We also provide an overview of salvage therapies for overt relapse, including targeted therapies, chemotherapies, immunotherapies, donor lymphocyte infusion, and selected agents under investigation in ongoing clinical trials. Finally, we review the evidence for a second alloSCT (HSCT2) and discuss factors that impact donor selection for HSCT2.