It has been more than 10 years since any new disease-modifying therapies have received regulatory approval for indications related to myelodysplastic syndromes (MDS). Advances in our collective biological understanding of MDS in the last decade, however, have made it possible to hope that effective therapeutics can be designed to improve MDS-associated cytopenias and patients' quality of life, and perhaps even delay clonal progression and extend survival. Classes of MDS-associated mutations and disordered biological pathways targeted by developmental therapeutics include the following: aberrant messenger RNA splicing, neomorphic enzymes in the citric acid cycle with oncogenic activity, overactivated tyrosine and serine-threonine kinases, epigenetic and chromatin remodeling alterations, abnormal telomere dynamics, and failed protection of DNA integrity. At present, treatments for MDS are usually administered as sequential monotherapy, but there is a trend toward clinical trials of combination therapies-in which new agents are added to a DNA hypomethylating agent backbone-for both upfront treatment and the treatment of relapsed/refractory disease. Agents in clinical trials for subsets of MDS include luspatercept, antibodies targeting CD33, isocitrate dehydrogenase inhibitors, deacetylase inhibitors, venetoclax, and immunotherapies designed to overcome immune checkpoint inhibition. These biologically based therapeutics, as well as the encouraging precedent of 7 new approvals by the US Food and Drug Administration in 2017 for the treatment of acute leukemia, offer the prospect that 10 more years will not elapse before another new therapy is approved for MDS.