The CREB binding protein (CBP) was first identified as a protein that specifically binds to the active phosphorylated form of the cyclic-AMP response element binding protein (CREB). CBP was initially defined as a transcriptional coactivator that, as a result of its large size and multiple protein binding domain modules, may function as a molecular scaffold. More recently, an acetyltransferase activity, both of histones and nonhistones, has been found to be essential for transactivation. In this review, we will discuss the current understanding of the acetyltransferase specificity and activity of the CBP protein and how it may function to coactivate transcription. We will also examine the regulation of the CBP histone acetyltransferase activity in the cell cycle, by signal-transduction pathways and throughout development.