Hypomethylating agents (HMAs) are the standard of care for higher-risk myelodysplastic syndrome (MDS) patients in whom azacitidine was the only treatment to demonstrate an overall survival advantage in a randomized clinical study. Only 40% to 50% of patients typically will respond to HMAs, with a median duration of response < 1.5 years and eventually all patients will lose initial response. Outcome after HMA treatment failure is poor and represents an unmet need. In this article we review the definition of HMA failure in higher-risk MDS patients and its outcome. We highlight options of treatment including sequential use of HMAs, add-back strategies, other palliative chemotherapy options, and provide an overview for several promising investigational agents. Understanding mechanisms of resistance and molecular changes at the time of HMA failure will be a key to development of further therapies.