Recent studies have demonstrated that myelodysplastic syndromes (MDS) arise from a small population of disease initiating hematopoietic stem cells (HSCs) that persist and expand through conventional therapies and are major contributors to disease progression and relapse. MDS stem and progenitor cells are characterized by key founder and driver mutations and are enriched for cytogenetic alterations. Quantitative alterations in stem and progenitor numbers are also seen in a stage specific manner in human MDS samples as well as in murine models of the disease. Overexpression of several markers such as IL1RAP, CD99, TIM3, CD123 have begun to differentiate MDS HSPCs from healthy counterparts. Overactivation of innate immune components such as TLRs, IRAK/TRAF6, IL8/CXCR2 and IL1RAP signaling pathways has been demonstrated in MDS HSPCs and are being targeted therapeutically in preclinical and early clinical studies. Other dysregulated pathways such as STAT3, Tie2/Angpt1, PAK1, miR-21 and TGF-beta pathways are also being explored as therapeutic targets against MDS HSPCs. Taken together, these studies have demonstrated that MDS stem cells are functionally critical for the initiation, transformation and relapse of disease and need to be targeted therapeutically for future curative strategies in MDS.