The clinical data from abiraterone acetate and enzalutamide confirm continued androgen receptor (AR) addiction in a significant proportion of castration-resistant prostate cancers (CRPC). Abiraterone acetate is a specific inhibitor of CYP17A1 and results in significant suppression of serum androgenic steroids and estrogen. Enzalutamide is a potent AR antagonist. Both agents improve the survival of CRPC patients. However patients invariably progress, often with a rise in PSA suggesting resumption of transcription of hormone-regulated genes. If abiraterone or enzalutamide-resistant cancers remain addicted to steroid receptor signaling, including but not exclusive to AR, how does reactivation occur? Or if cancers lose this addiction, do the same hormone-regulated oncogenic mechanisms continue to drive the disease? The future development of therapeutics for CRPC should be informed by an understanding of the mechanisms underlying disease progression following treatment with these novel agents. Tumor responses are being observed with sequential targeting of AR or steroidogenesis after abiraterone or enzalutamide but preliminary reports suggest lower response rates. This highlights the requirement for patient selection for future successful Phase III trials. Our experience with obtaining CRPC tumor biopsies and using them for molecular characterization will be discussed together with data obtained from circulating biomarkers including circulating tumor cells and circulating plasma nucleic acids.