Hypomethylating agents (HMAs) improve the outcome of higher-risk myelodysplastic syndromes (MDS) and provide multilineage response in lower-risk patients but their results must be optimized, especially as the poor outcome of patients after HMA failure is now established.Current efforts include evaluation of novel outpatient administration schedules and routes, improving compliance and drug exposure to reach continuous hypomethylation. Novel combination strategies are emerging, with histone deacetylase inhibitors or immunomodulatory compounds, but none has proven superior to HMA single-agent therapy so far. Improved understanding of the epigenetic deregulation of MDS and of HMA's mode of action has allowed putative biomarkers to emerge, including multiple gene methylation patterns, and gene mutations, notably TET2 mutations. As HMAs may elicit antileukemic immune responses, they are also being evaluated in patients eligible for allogeneic stem cell transplantation.The indication and practical use of HMAs in MDS so far remain those of phase III registration studies, but will hopefully be modified with future results of ongoing clinical and translational research.