The clinical data from abiraterone acetate and MDV-3100 confirm continued androgen receptor (AR) addiction in a significant proportion of castration-resistant prostate cancers (CRPC). However, patients nearly invariably progress with a rise in prostate-specific antigen, suggesting resumption of transcription of hormone-regulated genes. If CRPC remains addicted to steroid receptor signaling, including, but not exclusive, to AR, how does reactivation occur? Or if cancers lose this addiction, do they remain driven by the same oncogenic mechanisms? 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.