To guide development of new clinical strategies, a review of recent investigations in the pathobiology of MDS was performed. Articles were identified through a Medline search. Studies, including reviews, are cited in the references. A multistep pathogenesis is proposed. (1) Targeted injury or mutation within hemopoietic stem cells may be followed by an immunologic response adversely affecting progenitor survival. (2) Accelerated proliferation and premature death of marrow cells is amplified by apoptogenic cytokines (TNF-alpha, Fas ligand). (3) Establishment of an abnormal clone associated with telomere shortening. (4) Disease progression associated with loss of tumor suppressor activity. Opportunities for therapeutic interventions are possible at each step. Comparisons between the proposed pathogenesis of MDS and severe aplastic anemia (SAA) are also presented. Leukemia (2000) 14, 2-8.