Higher-risk myelodysplastic syndromes (MDS) are defined as patients who fall into higher risk group categories in the original or revised International Prognostic Scoring System (IPSS). Survival for these patients is dismal, and treatment should be initiated rapidly. Standard therapies include the hypomethylating agents azacitidine and decitabine, which should be administered for a minimum of 6 cycles, and continued for as long as a patient is responding. Once a patient fails one of these drugs, options are limited, median survival is less than 6 months, and consideration should be given to clinical trials. Higher-risk eligible patients should be offered consultation to discuss hematopoietic stem cell transplantation close to the time of diagnosis, depending on patient goals of therapy, with consideration given to proceeding to transplantation soon after an optimal donor is located. In the interim prior to transplantation, hypomethylating agent therapy, induction chemotherapy or a clinical trial should be considered to prevent disease progression, although the optimal pre-transplantation therapy is unknown.