Myelodysplastic syndromes/neoplasms (MDS) are a widely heterogenous group of myeloid malignancies characterized by morphologic dysplasia, a defective hematopoiesis, and recurrent genetic abnormalities. The original and revised International Prognostic Scoring Systems (IPSS) have been used to risk-stratify patients with MDS to guide treatment strategies. In higher-risk MDS, the therapeutic approach is geared toward delaying leukemic transformation and prolonging survival. For over a decade, the hypomethylating agents azacitidine and decitabine have been the standard of care and, when feasible, an allogeneic hematopoietic stem cell transplantation (AHSCT) should be considered. However, the IPSS scoring systems solely rely on clinical, morphological, and cytogenetic features and do not account for somatic mutations present in over 80% of cases. These genetic abnormalities have been shown to play a crucial role in prognostication, prompting the development of molecular IPSS, and the integration of genomic features into MDS classification systems in recent years. In this review, we delineate our approach to higher-risk MDS in the context of updated classifications and the latest prognostication tools. We employ illustrative clinical cases to support our discussion and share insights from recent clinical trials, highlighting lessons learned.