Differentiation of pluripotent hematopoietic stem cells into mature circulating blood cells is coordinated by a complex series of transcriptional events. During the last decade, numerous transcription factors have been identified whose expression is highly lineagerestricted within the hematopoietic system. These include the GATA family of transcription factors, NF-E2, EKLF, the C/EBP family of proteins, EKLF, and AML-1. 1, 2 However, tissue-specific and developmentally correct expression of a given gene is not achieved by a single transcription factor. Rather, unique combinations of cell-type specific and widely expressed nuclear factors account for the enormous specificity and diversity in gene expression profiles. Recently, 2 highly related and widely expressed molecules, CREB-binding protein (CBP) and p300, have emerged as important cofactors for a broad number of transcription factors both within and outside the hematopoietic system. Haploinsufficiency of CBP results in Rubinstein-Taybi Syndrome (RTS) in humans, a disease characterized by mental retardation, craniofacial abnormalities, broad toes and thumbs, and an increased propensity for malignancies, including those derived from the hematopoietic system. 3 Mice heterozygous for a disrupted CBP gene display a phenotype similar to RTS, 4 and have an increased incidence of leukemias and histiocytic sarcomas. 5 Mice lacking both CBP alleles die during embryonic development and display severe defects in primitive and definitive hematopoiesis, and in vasculo-angiogenesis. 6 Chromosomal translocations involving the CBP and p300 genes are associated with certain forms of leukemia, underscoring the importance of these genes in the regulation of hematopoietic cell differentiation and proliferation. A series of recent reviews 7-9 serve as excellent guides through the large number of factors interacting with CBP and p300. This review will focus on the role of CBP and p300 in the transcriptional control of hematopoietic cell differentiation. After a general overview of CBP and p300, the hematopoietic transcription factors regulated by CBP and p300 are described in a systematic fashion. Subsequently, human diseases involving the CBP and p300 genes and animal models related to these diseases are described. This is followed by an attempt to conceptualize our knowledge by discussing mechanistic aspects of CBP and p300 function.