To respond to changes in its environment, the cell utilizes mechanisms that integrate extracellular signals with specific changes in gene expression. To better understand these critical regulatory mechanisms, research has focused, for the most part, on the identification of sequence-specific DNA-binding proteins, such as the nuclear factor kappaB (NF-kappaB) or activator protein 1 (AP-1) families of transcription factors, that interact with the promoter and enhancer elements of genes induced or repressed during cellular activation. More recently, however, it has become apparent that non-DNA-binding transcriptional coactivators, such as p300 and CREB binding protein (CBP), previously thought to function primarily as "bridging" proteins between DNA-bound transcription factors and the basal transcription complex, play a critical regulatory role as integrators of diverse signalling pathways with the selective induction of gene expression. In this commentary, we shall discuss the implications of a particular aspect of this growing and expanding field: how cell cycle regulation of p300 and CBP impacts our understanding of cellular differentiation, the response to DNA damage, and oncogenesis.