The complete reliance on praziquantel to treat schistosomiasis represents a global vulnerability in the sustainable control of this neglected disease, especially in the case that praziquantel resistant schistosomes develop. In the absence of a vaccine, and with very little new chemical matter being progressed into late-stage preclinical investigations, this situation presents a substantial challenge for the teams of medicinal chemists and parasitologists seeking to identify praziquantel replacements as part of collaborative drug discovery initiatives. Historically, the main approach to identifying anti-schistosomal compounds has relied on phenotypic screening, where the cellular target of the compound is (at least initially) unknown. More recently, efforts have been made to identify S. mansoni targets that can be modulated for therapeutic benefit, or to repurpose molecules that target a specific class of human proteins. As a digenetic parasite, S. mansoni has adopted a lifecycle comprised of distinct morphological forms to maximise survival in a range of harsh environments, including the intermediate host snail, the definitive mammalian host, and fresh-water bodies. The phenotypic changes that accompany lifecycle progression occur without alteration of its genetic code, suggesting that the parasite's epigenetic machinery plays a key role in these processes. We reasoned, therefore, that BRD-containing epigenetic regulators could be therapeutically interesting targets for the development of anti-schistosomal compounds. Having identified 29 BRDs in S. mansoni we have begun a systematic investigation into their function. Our approach of focusing on SmBRD3, which is the S. mansoni BRD that is most similar to the human BET BCPs, was validated by the identification of high affinity ligands for both SmBRD3(1) and