Even though the pathogenesis of myelodysplastic syndromes (MDS) is dominated by an inefficient maturation of haematopoietic precursors, also immune mechanisms seem to play a crucial functional role. In this review, we will first describe the clinical and laboratory autoimmune manifestations often detectable in MDS patients. We will then focus on studies addressing the mechanisms of T-cell activation and their implications in the disease history. The potential impact of specific cell subsets, such as regulatory T-cells, Th17 cells and natural killer cells, will be also described. We will finally focus on potential therapeutic approaches based on immunomodulation, ranging from more classical immunosuppressive drugs to vaccination and transplantation strategies.