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Myelodysplastic syndrome (MDS) are clonal myeloid neoplasms that cause cytopenias and can progress to acute myeloid leukemia (AML). Hypomethylating agents (HMA) are the mainstay of treatment for higher risk disease, but they achieve responses in only half of treated patients and complete remission rates are low. Several scientifically based combinatorial regimens have been tested in clinical trials but none has demonstrated a survival benefit over HMA monotherapy. Allogeneic stem cell transplant remains the only curative therapy and is dependent on effective donor lymphocytes for its efficacy. However, access is limited by its toxicity, so alternative approaches are sorely needed. Recent clinical and translational studies have shown that MDS is not only a clonal myeloid disorder, but also associated with immune dysregulation, inflammatory signaling, T-cell repertoire restriction, immune exhaustion, and immune mediated suppression of hematopoiesis. These findings suggest that there is potential for unlocking a novel approach to the treatment of MDS by restoring and/or enhancing the lymphoid immune response. In this review, we discuss the current understanding of the role of normal T lymphocytes in MDS, the causes and manifestations of dysfunctional T lymphocytes as well as the role and dysfunction of natural killer (NK) cells. The role of therapeutic immunosuppression in lower risk MDS is reviewed, as is the impact of HMAs on dysregulated T lymphocytes and NK cells in higher risk disease. We propose that there is tremendous potential for more targeted approaches to engage the lymphoid compartment in addressing the unmet therapeutic need in MDS.