Myelodysplastic syndrome (MDS), an acquired clonal disorder of haemopoietic progenitor cells, is characterized by haemopoietic insufficiency associated with cytopenias, leading to serious morbidity plus the additional risk of leukaemic transformation. In MDS an acquired insult to the haemopoietic stem cell leads to impaired differentiation and myelodysplasia. However, there is increasing evidence that the marrow failure of MDS is immune-mediated. A model of MDS pathophysiology suggests that transformation of normal stem cells induces an autoimmune T-cell response with the bone marrow as the target organ. This autoimmune attack results in chronic overproduction of pro-apoptotic cytokines, especially tumour necrosis factor alpha (TNFα). In addition, several reports have revealed that approximately 10% of MDS patients have clinical autoimmune disorders. This review illustrates the cellular/molecular mechanisms and the implication of the tumour suppressor gene interferon regulatory factor-1 (IRF-1) in the pathophysiology of MDS-associated autoimmune deregulation.