Myelodysplastic syndrome (MDS) refers to a group of clonal disorders affect both hematopoietic stem cells and progenitor cells within the erythrocytic, granulocytic, and megakaryocytic lineages. Ineffective hematopoiesis, the major manifestation of MDS, arises from a complex interaction between hematopoietic progenitors and the microenvironment, resulting in premature apoptotic death of progenitors and their maturing progeny. Development and progression of MDS is suggested to be a multistep alteration to hematopoietic stem cells. Although the molecular pathogenesis of MDS has not been clearly elucidated, a model of MDS pathogenesis has been proposed whereby a normal hematopoietic stem cell acquires successive genetic abnormalities that ultimately lead to malignant transformation and clonal expansion. Early mutations in stem cells may cause differentiation arrest and apoptosis leading to dysplasia and cytopenia, wherease subsequent defects affecting myeloid cell proliferation may cause the clonal expansion of aberrant cells and leukemic transformation. The heterogeneity in the clinical and morphologic features in MDS reflects the diversity and complexity of the underlying genetic defects. Some of these different molecular alterations have been described. However, since the developing targeted therapeutic advances in MDS will likely depend on a full comprehension of underlying molecular mechanisms, it may be required to make further progress in understanding the exact pathomechanisms of this disease. (Korean J Med 76:115-120, 2009)