Myelodysplastic syndromes (MDS) are characterized by dysplastic morphologic features and ineffective hematopoiesis. Pathophysiological characteristics change over time making therapeutic development a major challenge. In early MDS, cytopenias arise or are exacerbated by humoral and cellular immune-mediators that suppress hematopoietic progenitor survival and alter the bone marrow microenvironment. Areas covered: In this review, current immunosuppressive regimens are described. To identify new therapies that may enhance immunosuppressive therapy (IST) response and identify pharmacodynamic biomarkers for patient selection, the inflammasome, cytokines, metabolic pathways and signaling events are described. Expert opinion: Agents with the potential to induce early, durable hematologic remissions are needed and many new immunosuppressive agents are available for investigation. An immune-mediated mechanism is likely to contribute to MDS early after diagnosis. New approaches that interfere with inflammatory pathways in the bone marrow microenvironment may move closer toward sustained disease control in MDS.