Heterogeneity is the disease-defining epithet of myelodysplastic syndromes (MDS), a clonal disorder of hematopoietic stem and progenitor cells. During the last decade, significant progress has been made to better understand the diversity of clinical, molecular, cellular, and immunological factors that are bound to the prognosis and outcomes of patients with MDS. Despite the rapid generation of all of this biological information, how to implement it has fallen short. Redefining clinical tools to use this new information remains a challenge. The holistic integration of novel, high-impact individual risk parameters such as patient-reported outcomes or mutational and immunological data into conventional risk stratification systems may further refine patient subgroups, improve predictive power for survival, and provide a next-generation classification and prognosis system for patients with MDS. Dichotomic treatment strategies in patients with MDS according to their patient and disease profiles highlight the importance of precise risk stratification, which may be complemented by the definition of granular cohorts of patients with myeloid neoplasms and a druggable target (ie, IDH1/2 mutations) across conventional blast thresholds.