Advanced and metastatic prostate cancers remain potentially lethal tumors. Although androgen deprivation therapy remains the most effective treatment, patients who progress to androgen independence die of their disease. This article focuses on the mechanisms by which hormone resistance develops, including the reactivation of androgen receptor during androgen deprivation therapy, the role of cancer stem cells, and the emergence of epithelial-mesenchymal transition cells, which have increased metastatic potential. It is through an enhanced understanding of these mechanisms that new therapies can be developed to combat this disease.