Despite advances made over the years in the pharmacotherapy of prostate cancer, progression to the advanced phenotypes which ultimately account for the high rate of mortality in patients continue to pose a significant challenge to clinical management and outcomes. Recent integrative strategies geared towards the identification of beneficial molecules have identified the role of epigenetics and in turn BET proteins in the disease progression. In this review, we explored the role of BET protein paralogs in prostate tumorigenesis and proceeded to probe pharmacotherapeutic targeting of BET proteins using small molecule inhibitors with emphasis on computational techniques employed. Finally, we explored the relevance of various computational techniques to uniquely classify bromodomain-containing protein–targeted molecules with efficacy in advanced prostate cancer. Our opinion is that many small molecule inhibitors of BET proteins have been identified with some making it to clinical trials, albeit unsuccessfully. Although several computer-aided drug design (CADD) techniques have been employed, the continuous integration of CADD will only serve to improve on efforts already made towards the design of efficacious, potent, and highly selective novel BET inhibitors as witnessed recently in the suppression of treatment-emergent neuroendocrine prostate cancer (NEPC) by BRD4 inhibitors.