Patients with higher-risk myelodysplastic syndrome (HR-MDS) are defined by the original or revised International Prognostic Scoring System and specific genetic features. Treatment of HR-MDS is challenging. Allogeneic hematopoietic stem cell transplantation, the only curative approach, is feasible in a minority of fit or intermediate fitness patients aged <70 to 75 years who are willing to face the risks of the procedure. Response to azacitidine and decitabine, the only approved drugs for HR-MDS and considered the standard of care, is partial and transient in most patients. The development of novel more personalized and efficient drugs is an unmet medical need. During the last decade, there have been substantial advances in understanding the multiple molecular, cellular, and immunological disturbances involved in the pathogenesis of myelodysplastic syndrome. As a result, a number of clinical and translational studies of new more focused treatment approaches for HR-MDS patients are underway. In contrast to acute myeloid leukemia, they have not resulted in any new drug approval. This review addresses the benefits and limitations of current treatment alternatives, offers a practical individualized treatment approach, and summarizes the clinical trials in progress for HR-MDS.