Although organ-confined, moderately-graded prostate cancer has encouraging cure rates, progression to castration-resistant prostate cancer (CRPC) from advanced, high-grade prostate cancer represents the lethal form of this malignancy, for which current therapeutic modalities are only palliative; patients with CRPC will die from their disease. Our work has identified SOX2, a transcription factor vitally important for embryonic stem cell maintenance and programming, to play a central yet novel and undefined role in driving CRPC.