The initiation processes for the development of MDS remain unknown. A poorly defined transforming event affects a pluripotent or multipotent progenitor cell in the bone marrow, conferring a growth advantage upon it and eventually establishing clonal hematopoiesis. An important pathogenetic mechanism in MDS is premature intramedullary cell death via excessive apoptosis, explaining the apparent paradox of a cellular marrow in combination with peripheral cytopenias (ineffective hematopoiesis). Therapy-related MDS/AML following exposure to alkylating agents is the only clear etiological factor thus identified. Increasing evidence for exposure to benzene and radiation and the development of MDS is emerging. Benzene hematotoxicity is mediated via both genotoxic and non-genotoxic mechanisms, leading to aplasia, apoptosis and initiation (via genetic mutation) of clonal disorders such as MDS. Further studies of benzene hematotoxicity and therapy-related MDS should provide models for the elucidation of initiation events in MDS pathogenesis. The importance of such studies is emphasized by the rising frequency of MDS which largely reflects improved diagnostic criteria, increased physician awareness and extended use of diagnostic procedures in the elderly. Demographic changes will lead to a marked increase in MDS over the next few decades.