Given prostate cancer is driven, in part, by its responsiveness to androgens, treatments historically employ methods for their removal from circulation. Approaches as crude as castration, and more recently blockade of androgen synthesis or receptor binding, are still of limited use long term, since other steroids of adrenal origin or tumor origin can supersede that role as the 'castration resistant' tumor re-emerges. Broader inhibition of steroidogenesis using relatively nonselective P450 inhibitors such as ketoconazole is not an alternative since a general disruption of steroid biosynthesis is neither safe nor effective. The recent emergence of drugs more selectively targeting CYP17 have been more effective, and yet extension of life has been on the scale of months rather than years. It is now becoming clear this shortcoming arises from the adaptive capabilities of many tumors to initiate local steroid synthesis and/or become responsive to novel early pathway adrenal steroids that are synthesized when lyase activity is not selectively blocked, and ACTH rises in the face of declining cortisol feedback. Abiraterone has been described as a lyase selective inhibitor, yet its use still requires co-administration of prednisone to suppress such a rise of ACTH and fall in cortisol. So is creation of a selective lyase inhibitor even possible? Can C19 steroid production be achieved without a prominent decline in cortisol and corresponding rise in ACTH? Decades of scientific study of CYP17 in humans and nonhuman primates, as well as nature's own experiments of gene mutations in humans, reveal 'true' or 'isolated' 17,20 lyase deficiency does quite selectively prevent C19 steroid biosynthesis whereas simple 17 hydroxylase deficiency also suppresses cortisol. We propose these known outcomes of natural mutations should be used to guide analysis of clinical trials and long term outcomes of CYP17 targeted drugs. In this review, we use that framework to re-evaluate the basic and clinical outcomes of many compounds being used or in development for treatment of castration resistant prostate cancer. Specifically, we include the nonselective drug ketoconazole, and then the CYP17 targeted drugs abiraterone, orteronel (TAK-700), galaterone (TOK-001), and seviteronel (VT-464). Using this framework, we can fully discriminate the clinical outcomes for ketoconazole, a drug with broad specificity, yet clinically ineffective, from that of abiraterone, the first CYP17 targeted therapy that is limited by its need for prednisone co-therapy. We also can identify potential next generation CYP17 targeted drugs now emerging that show signs of being far more 17,20 lyase selective. We conclude that a future for improved therapy without substantial cortisol decline, thus avoiding prednisone co-administration, seems possible at long last.