In eukaryotic cells, gene transcription is regulated by sequence-specific DNA-binding transcription factors that recognize promoter and enhancer elements near the transcriptional start site. Some coactivators promote transcription by connecting transcription factors to the basal transcriptional machinery. The highly conserved coactivators CREB-binding protein (CBP) and its paralog, E1A-binding protein (p300), each have four separate transactivation domains (TADs) that interact with the TADs of a number of DNA-binding transcription activators as well as general transcription factors (GTFs), thus mediating recruitment of basal transcription machinery to the promoter. Most promoters comprise multiple activator-binding sites, and many activators contain tandem TADs, thus multivalent interactions may stabilize CBP/p300 at the promoter, and intrinsically disordered regions in CBP/p300 and many activators may confer adaptability to these multivalent complexes. CBP/p300 contains a catalytic histone acetyltransferase (HAT) domain, which remodels chromatin to 'relax' its superstructure and enables transcription of proximal genes. The HAT activity of CBP/p300 also acetylates some transcription factors (e.g., p53), hence modulating the function of key transcriptional regulators. Through these numerous interactions, CBP/p300 has been implicated in complex physiological and pathological processes, and, in response to different signals, can drive cells towards proliferation or apoptosis. Dysregulation of the transcriptional and epigenetic functions of CBP/p300 is associated with leukemia and other types of cancer, thus it has been recognized as a potential anti-cancer drug target. In this review, we focus on recent exciting findings in the structural mechanisms of CBP/p300 involving multivalent and dynamic interactions with binding partners, which may pave new avenues for anti-cancer drug development.