Higher-risk myelodysplastic syndromes (MDS) are a collection of diseases associated with poor outcomes from complications related to bone marrow failure and evolution to acute myeloid leukemia. While most patients receive epigenetic therapies, intensive chemotherapy or allogeneic stem cell transplantation, more tolerable and effective treatments are necessary to realize the goal of stopping this disease in its tracks. Recent efforts, building on decades of research exploring the pathogenesis of this disease, have revealed exciting clues that elucidate critical biological features that drive or contribute to MDS, and may serve as targets for selective and well-tolerated future therapies. Here, we review the current diagnostic, prognostic, and therapeutic approaches to higher-risk MDS.