The Rb tumor suppressor pathway is functionally inactivated in most human cancers. In human blood cancers, loss of Rb expression has been widely reported in both acute myeloblastic and acute lymphoblastic leukemias, cyclin D1 amplification is common in mantle cell lymphoma, and silencing of the p16/INK4a tumor suppressor gene occurs frequently in AML and various types of lymphoma. Silencing of p16/INK4A expression is frequently caused by hyper-methylation of CpG islands in its promoter but may also be achieved through activation of Bmi-1, for example in lymphomas associated with the E2A-Pbx1 translocation. Hematopoietic homeostasis ensures a balance between proliferation and differentiation at different levels within the hematopoietic hierarchy such that hematopoietic stem cell self-renewal, progenitor proliferation and terminal differentiation to functional blood cells are maintained throughout the life of the animal. Leukemic transformation disrupts this balance favoring proliferation over differentiation, but the mechanisms underlying cell cycle regulation and checkpoint control in the hematopoietic system are not understood. Recent data from our laboratory has identified a unique role for the Rb tumor suppressor gene in the response to anemic and oxidative stress that has implications not just for red cell production but for the homeostatic balance in the entire hematopoietic system and for the development of hematopoietic malignancies.