The androgen receptor (AR) is important for the growth and survival of normal and malignant prostate cells. As such, androgen-deprivation therapy is the current mainstay of systemic prostate cancer therapy. Invariably, prostate cancer will develop resistance to androgen deprivation and recur with a castration-recurrent phenotype. The surprising finding that castration-recurrent prostate cancer is still reliant on AR activity indicates that novel means of targeting the AR could be developed to treat this stage of the disease. Several mechanisms, including ligand-independent activation, have been described as means by which the AR can achieve a critical level of activity in castration-recurrent prostate cancer. This chapter will explore the mechanisms of ligand-independent AR activation and highlight some recent findings generated in the Tindall laboratory.