Functional androgen receptor (AR) signaling is necessary for the development of prostate cancer. The therapeutic effect of androgen deprivation therapy for prostate cancer was described over 60 years ago and this treatment remains the mainstay of systemic therapy despite its transient response duration. It has become clear that AR expression and signaling remains intact as the disease evolves from androgen-sensitive cancer to classically (but perhaps inaccurately) termed hormone refractory prostate cancer. Through several genetic and epigenetic adaptations, prostate tumors continue to rely on AR growth signaling and they thus remain targets of 'hormonal' therapy. The development of new strategies and drugs that can abrogate AR signaling will probably result in important clinical benefits. The biology of androgen independence and the development of new approaches targeting AR signaling are reviewed herein.