Due to its pivotal role in prostatic growth and survival, the androgen receptor (AR) is the primary target of disseminated prostate cancer (CaP), as achieved via androgen deprivation therapy (ADT). Unfortunately, ADT is circumvented by restoration of AR activity, resulting in ADT resistant tumors for which there is no alternate treatment option. Through multiple mechanisms, reactivation of the AR specifically underlies the progression to therapy resistant tumors. The environmentally prevalent endocrine disrupting compound (EDC), bisphenol A (BPA) is able to activate specific somatically mutated ARs commonly found in CaP, resulting in androgen-independent proliferation of CaP cells. To directly assess the effect of BPA on ADT, we used an in vivo xenograft model of CaP that expresses a BPA-sensitive mutant AR, and mimics standard human cytotoxic response to ADT, followed by subsequent tumor re-growth. When tumor-bearing animals were exposed to environmentally relevant levels of BPA during ADT, the tumors failed therapy more rapidly (compared to placebo controls), with AR re-activation and concomitant increased tumor cell proliferation. These data suggest that environmentally relevant exposure to EDCs may reduce the efficacy of mainline ADT for CaP. We next determined that the environmentally persistent pesticide, DDE, was able to activate select AR mutants, and in in vitro models of CaP, DDE induces cellular proliferation in the absence of androgen, demonstrating that this observed response was not unique to BPA. Strikingly, the mechanism of DDE impact on CaP cells was distinct from BPA, in that at low doses this agent also activated the MAPK pathway, and requires this activation for mitogenesis. Given the context specific impact of AR activation by EDCs, and the deleterious effect of exposure to BPA on ADT in vivo, we next addressed the impact of AR action on taxane-based therapy. These cytotoxic agents have recently been shown to improve survival outcome for patients with advanced CaP, and are potentially new second line therapies, however the impact of AR action on this cytotoxic modality had yet to be assessed. Contrary to the stigma of AR as a survival factor, we found that AR activation by both endogenous and exogenous agonists (i.e. DHT and BPA), synergized with taxanes to decrease cell survival, through p53-mediated, caspase dependent apoptosis. This synergistic action was attributed directly to the AR-dependent mitogenic capacity of these agents. Importantly, these data further support the conclusion that the environmental impact on AR action and CaP therapeutic outcome is context specific. We further evaluated the complexity of EDC affects by assessing the impact of these agents under clinically relevant conditions in another hormone-dependent tissue, breast cancer. BPA and the phytoestrogen, coumestrol (COU), were able to activate the estrogen receptor (ER-alpha), but this activation was restricted to estrogen-depleted conditions, and could be blocked by the standard ER antagonist, tamoxifen. Additionally, BPA and COU have disparate affects in multiple analyses including mutant ER-alpha activation, and specific coactivator deregulation. In conclusion, the environmental impact on nuclear receptor signaling and hormone dependent cancer progression and treatment is highly molecular context specific. Therefore, the impact of EDCs on hormone dependent cancer treatment needs to be identified under specific and well defined, clinically relevant, molecular contexts.