p300 and CBP are highly homologous coactivators which promote gene transcription by bridging between DNA-binding transcription factors and the basal transcription machinery, by providing a scaffold for integrating transcription factors, and by modifying transcription factors and chromatin through acetylation. The p300/CBP cofactors are involved in a plethora of physiological processes, and their activity is essential for embryogenesis. Chromosomal translocations affecting the p300 and Cbp genes are the cause of hematological malignancies, and Cbp haploinsufficiency is a hallmark of the Rubinstein-Taybi syndrome. In addition, mutations in the Cbp or p300 gene, accompanied by loss of the other allele, have been found in various kinds of tumors. Furthermore, inhibition of CBP and p300 function in neurodegenerative diseases caused by polyglutamine expansion may be an underlying cause for cytotoxicity. Approaches to modulate p300/CBP function may be instrumental in the development of novel therapies directed against viral infections, cancer and neurodegenerative diseases.