Although most solid tumors contain inactivating mutations of the p53 tumor suppressor, hematological malignancies do not contain frequent alterations in the p53 gene (<20%). How these tumors arise in the presence of a super tumor suppressor like p53 remains to be elucidated. Given the number of downstream effectors of p53, it is likely that critical targets of p53 are inactivated in leukemia, bypassing the requirement for p53 gene mutations in these tumors. This review describes new biochemical and transcriptional activities of p53 as well as the status of p53 in acute myelogenous leukemia and chronic myelogenous leukemia.