Hypomethylating agents (HMAs) are the mainstay treatment of patients with myelodysplastic syndromes. Hypomethylating agents remain the only treatment, other than allogeneic hematopoietic stem cell transplantation (AHSCT), that improves overall survival (OS) for patients with higher-risk myelodysplastic syndromes. It is crucial to maximize the benefit of HMAs by selecting the appropriate dosing and schedule and continuing therapy until clear evidence of lack of response or failure of therapy. Strategies to improve outcome with HMAs include identifying tools and biomarkers for better patient selection, namely the ability to identify those who achieve complete response (CR) or long duration of response, combination strategies with HMAs aim to improve response rate or its duration. The outcome of patients with myelodysplastic syndromes after HMA failure is poor for both patients with higher-risk and lower-risk disease and represents an unmet medical need. The best outcomes after HMA failure are reported with AHSCT or novel agents in clinical trials. This article discusses the maximizing benefit of HMAs, offers strategies to improve outcome with HMAs, and, finally, reviews selected novel agents in development after HMA failure.