The oncoprotein SET/TAF-I beta is a histone chaperone which is involved in cell-cycle control and chromatin remodeling. Confocal laser scanning microscopy reveals that SET is localized in distinct foci of variable size throughout the nucleoplasma of interphase cells. We report here that SET interacts directly with the acetyltransferase CREB-binding protein (CBP) and enhances the transactivation potential of the transcription coactivator. Our data suggest that the histone chaperone SET regulates the CBP-mediated transcription and may indicate a general principle by which transcriptional regulators cooperate with historic chaperones for gene activation. (c) 2005 Elsevier Inc. All rights reserved.