While androgen deprivation therapy (ADT) remains the primary treatment modality for patients with metastatic prostate cancer (PCa), treatment is uniformly marked by progression to castration-resistant prostate cancer (CRPC). Accumulating data emphasize that androgen independent or hormone refractory tumors remain sensitive to hormonal activation and suggest that despite suppression of circulating testosterone (T), persistent activation of androgen receptor (AR) signaling plays a dominant role in driving progression. The introduction of novel agents targeting the AR signaling axis, including steroid synthesis inhibitors such as abiraterone and potent AR antagonists such as enzalutamide, have demonstrated striking responses in men with CRPC confirming the ongoing importance of AR signaling. However, not all patients respond, a majority develop clinical and PSA evidence of disease progression, and mechanisms of resistance to these agents are only beginning to be elucidated. In this presentation we will review AR-dependent mechanisms underlying disease progression, including tumoral appropriation of alternative androgen sources, alterations in AR expression, AR mutations, truncated AR variants, alterations and cross-talk in recruitment of co-factors to AR binding sites in the genome, and AR-driven oncogenic gene fusions. We will discuss the mechanism of action of new hormone-based therapies targeting the AR axis currently in clinical and pre-clinical development, and review emerging data that have begun to identify mechanisms of resistance to abiraterone and enzalutamide. Finally, we discuss current issues in the development of sequencing and combination treatment strategies, and in determining optimal patient selection for these agents. At the conclusion of this presentation the listener will 1) recognize the continued role of AR signaling in CRPC; 2) be able to identify tumor androgens and AR splice variants as key mechanisms mediating resistance to novel AR directed therapies, and 3) understand the opportunities for optimizing patient selection and the rationale for combination treatment strategies in the use of novel targeted agents in CRPC.