Prostate cancer (PCa) adapts to surgical or medical castration therapies (androgen deprivation therapy, ADT) that deplete testicular androgens by both increasing expression of androgen receptor (AR) and by increased intratumoral androgen synthesis. Therefore, although these tumors that relapse after castration are termed castrationresistant PCa (CRPC), they are still largely AR-dependent and androgen-dependent. Hence, they generally respond to agents that further decrease androgen levels by suppressing the synthesis of precursor steroids (CYP17A1 inhibitor abiraterone, ABI) or to direct AR antagonists such as enzalutamide (ENZ) or apalutamide (APA). On the contrary, although at least transient responses can be obtained in the majority of patients, most men recur within 1–2 years. A major focus of PCa research is now on the mechanisms that are driving resistance to these newer androgen-signaling inhibitors (ASIs), and on therapeutic approaches that may enhance the efficacy of AR-targeted therapies.