Epigenetic modification of chromatin structure underlies the differentiation of pluripotent hemopoietic stem cells (HSCs) into their committed/differentiated progeny. Compelling evidence indicates that Polycomb group (PcG) genes play a key role in normal and leukemic hemopoiesis through epigenetic regulation of HSC self-renewal/proliferation and commitment. The PcG proteins are constituents of evolutionary highly conserved molecular pathways regulating cell fate in several other tissues through diverse mechanisms, including 1) regulation of self-renewal/proliferation, 2) regulation of senescence/immortalization, 3) interaction with the initiation transcription machinery, 4) interaction with chromatin-condensation proteins, 5) modification of histones, 6) inactivation of paternal X chromosome, and 7) regulation of cell death. It is therefore not surprising that PcG genes lead to pleiotropic phenotypes when mutated and have been associated with malignancies in several systems in both mice and humans. Although much remains to be learned regarding the PcG mechanism(s) of action, advances in identifying the functional domains and enzymatic activities of these multimeric protein complexes have provided insights into how PcG proteins accomplish such processes. Some of the new insights into a role for the PcG cellular memory system in regulating normal and leukemic hemopoiesis are reviewed here, with special emphasis on their potential involvement in epigenetic regulation of gene expression through modification of chromatin structure.