Prostate cancer is a changeling disease. Although majority of patients show clinical and biochemical responses for long periods of time to therapies targeting the androgen receptor (AR), a small percentage of patients show intrinsic resistance. Moreover, despite dramatic responses, almost all patients will finally move from the hormone-sensitive state to the deadly castrate-resistant state, although in the castrate-resistant state, most tumours progress to AR targeted therapies through mechanisms involving the AR, but not all, and other pathways may become activated, being responsible for bypassing the AR inhibition. Once patients develop resistance to one AR targeted therapy, cross-resistance avoids in most of patients any further response to a different AR targeted therapy. The CARD trial has clearly proved that chemotherapy is superior to a sequence of AR targeted therapies in patients progressing after docetaxel and either enzalutamide or abiraterone in patients progressing before 1 year. Finally, olaparib has become the first targeted therapy not directed to the AR to prolong survival in selected patients with castrate-resistant prostate cancer. The aim of this study is to review the mechanisms of resistance to AR targeted therapies, the development of the castrate-resistant state and biomarkers to identify the castrate-resistant state and present and potential therapies to overcome the resistance to AR targeted therapies.