Polycomb proteins form DNA-binding protein complexes with gene-suppressing activity. They maintain cell identity but, also, contribute to the regulation of cell proliferation. Mice with mutated Polycomb-group genes exhibit various hematological disorders, ranging from the loss of mature B and T cells to development of lymphomas. Lymphopoiesis in humans is associated with characteristic expression patterns of Polycomb-group genes in defined lymphocyte populations. Collectively, these results indicate that Polycomb-group genes encode novel gene regulators involved in the differentiation of lymphocytes. The underlying mechanism is related, most probably, to gene silencing by chromatin modification, and might affect proliferative behavior and account for the irreversibility of lineage choice.