Prostate cancer is a leading cause of cancer death in men. While patients initially respond well to anti-androgen therapies, resistance is common. Here we identify a requirement for the transcriptional co-activators CBP/P300 for prostate cancer cell growth, which is maintained in the context of resistance to current therapy. In order to take therapeutic advantage of this vulnerability, we have developed a novel small-molecule inhibitor of the CBP/P300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment reveals a critical role for CBP/P300 in the histone acetylation required for AR transcriptional activity and target-gene expression. These findings strongly support CBP/P300 bromodomain inhibition as a therapeutic strategy in the treatment of castration resistant prostate cancer.