Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis with peripheral blood cytopenias, dysplastic cell morphology, and a variable risk of progression to acute myeloid leukemia (AML). The hypomethylating agents (HMA) azacitidine and decitabine have been used for over a decade in MDS treatment and lead to a modest survival benefit. However, response rates are only around 40% and responses are mostly transient. For HMA-refractory patients the prognosis is poor and there are no therapies approved by the United States Food and Drug Administration. Combinations of HMAs, especially along with immune checkpoint inhibitors, have shown promising signals in both the frontline and HMA-refractory setting. Several other novel agents including orally available and longer acting HMAs, the BCL-2 inhibitor venetoclax, oral agents targeting driver mutations (IDH1/2, FLT3), immunotherapies, and new options for intensive chemotherapy have been studied with variable success and will be reviewed herein. Except for the minority of patients with targetable driver mutations, HMAs - likely as part of combination therapies - will remain the backbone of frontline MDS treatment. However, the wider use of genetic testing may enable a more targeted and individualized therapy of MDS patients.