Prostate cancer is a significant cause of morbidity and mortality worldwide. Normal prostate tissue is regulated by androgens, which activate the androgen receptor, a nuclear receptor transcription factor. Most prostate tumors retain androgen dependence, therefore, current therapies for advanced prostate cancer either reduce androgen levels or prevent binding to the androgen receptor. Despite this regimen, prostate cancer invariably progresses to a fatal, androgen-refractory state. Although these relapsed tumors are androgen independent, they are still dependent on the androgen receptor for their growth and survival. The focus of this review will be to highlight our current understanding of the mechanisms of androgen receptor activation in androgen-refractory prostate cancer. How these mechanisms of androgen receptor activation could be targeted in this advanced stage of the disease is also discussed.