For most patients with higher-risk myelodysplastic syndromes (HR-MDS) the hypomethylating agents (HMA) azacitidine and decitabine remain the mainstay of therapy. However, the prognosis mostly remains poor and aside from allogeneic hematopoietic stem cell transplantation no curative treatment options exist. Unlike acute myeloid leukemia, which has seen a dramatic expansion of available therapies recently, no new agents have been approved for MDS in the United States since 2006. However, various novel HMAs, HMA in combination with venetoclax, immune checkpoint inhibitors, and targeted therapies for genetically defined patient subgroups such as APR-246 or IDH inhibitors, have shown promising results in early stages of clinical testing. Furthermore, the wider availability of genetic testing is going to allow for a more individualized treatment of MDS patients. Herein, we review the current treatment approach for HR-MDS and discuss recent therapeutic advances and the implications of genetic testing on management of HR-MDS.