According to recent estimates, a human cell has between 30,000 and 40,000 coding genes, but only a fraction of these are expressed in any cell lineage. Gene expression profiles of a given cell type undergo dramatic changes throughout development, differentiation, and the cell cycle, presenting the gene regulatory apparatus of a cell with a phenomenal degree of complexity. Cells deal efficiently with this enormous task by using transcriptional regulators in a combinatorial way. Thus, unique combinations of transcription factors convey specificity of gene expression and allow the use of each transcription factor at multiple gene loci. One advantage of this strategy is that even widely expressed transcription factors or cofactors can contribute to tissue-specific gene expression. The related transcription coactivators, CBP [cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-binding protein] and p300, are expressed widely and interact with a surprisingly large number of transcription factors via dedicated domains. As such, they could be viewed as general transcription regulators. Yet, loss of function and aberrant regulation or expression of CBP and p300 are associated with distinct phenotypes and diseases in humans and experimental organisms, indicating that certain genes/tissues are more sensitive to changes in CBP and p300 activity than others. Several thorough reviews provide a guide to the multitude of transcription factors regulated by CBP and p300 in various organisms [1–6]. Another recent review concentrates on the function of p300 and CBP during transcriptional regulation of hematopoietic development [7]. This review summarizes the functions of CBP and p300 in hematopoietic cells and the diseases associated with them. Special attention is given to erythroid gene expression, because it provides novel insights into lineagespecific gene expression and the function of enhancers and locus control regions (LCRs). Mechanistic aspects of CBP and p300 function are discussed in the context of their function in hematopoietic cells.