Prostate cancer (PCa) accounted for over 300 000 deaths world-wide in 2018. Most of the PCa deaths occurred due to the aggressive castration-resistant PCa (CRPC). Since the androgen receptor (AR) and its ligands contribute to the continued growth of androgen-dependent PCa (ADPCa) and CRPC, AR has become a well-characterized and pivotal therapeutic-target. Although AR signaling was identified as therapeutic-target in PCa over five-decades ago, there remains several practical issues such as lack of antagonist-bound AR crystal structure, stabilization of the AR in the presence of agonists due to N-terminus and C-terminus interaction, unfavorable large-molecule accommodation of the ligand-binding domain (LBD), and generation of AR splice variants that lack the LBD that impede the discovery of highly potent fail-safe drugs. This review summarizes the AR-signaling pathway targeted therapeutics currently used in PCa and the approaches that could be used in future AR-targeted drug development of potent next-generation molecules. The review also outlines the discovery of molecules that bind to domains other than the LBD and those that inhibit both the full length and splice variant of ARs.