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Relapse of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is associated with poor prognosis and remains the most common cause of treatment failure following allogeneic hematopoietic stem cell transplantation (alloHSCT). Over the past two decades, hypomethylating agents (HMAs), particularly azacytidine, have evolved from an experimental approach to the current therapeutic backbone of relapse therapy following alloHSCT, although future treatment paradigms may further evolve with emerging targeted and immunotherapeutic approaches. The RELAZA studies demonstrated that preemptive therapy with azacytidine in molecular relapse can significantly delay the onset of hematologic relapse. However, sustained disease control generally requires additional immunological mechanisms. Against this backdrop, the combination of azacytidine-either alone or in combination regimens-with donor lymphocyte infusions (DLI) has been established as a successful salvage strategy. Numerous studies have consistently shown over the years that a low disease burden, molecular rather than hematological relapse, and a longer interval between transplant and relapse are associated with better response rates and prolonged survival. This underscores the great importance of MRD monitoring for enabling early intervention. Prognostic models such as the APSS-R score incorporate these factors. Additionally, the score takes into account pre-transplant therapy, thereby underscoring the importance of a biologically tailored treatment strategy to prevent the emergence of treatment-resistant clones. Recent combination therapies with targeted agents, such as FLT3 and IDH inhibitors, as well as with venetoclax or lenalidomide, are showing promising results. Future strategies will likely focus on individualized, biological1ly guided treatment approaches and a selective indication for second alloHSCT.