The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival. Docetaxel was the first agent to demonstrate a survival improvement in this population, and other therapies followed (cabazitaxel, sipuleucel-T and radium-223). Understanding how prostate cancer cells grow in a systemic androgen-deprived environment further changed this clinical landscape. Deciphering what steroidogenic enzymes are overactive and required for testosterone/dihydrotestosterone synthesis has yielded therapies directed toward both adrenal and tumor-derived androgens. All androgens normally act through AR, and this fact remains true in mCRPC. The cancer accomplishes this by overexpressing the receptor (by genomic copy-number gains or RNA amplification), mutating it directly to lose its selectivity for testosterone/dihydrotestosterone, or selecting for splice variants that do not require ligand at all. These resistance mechanisms result in persistent AR-mediated signaling. Through this understanding, drugs targeting non–ligand-binding aspects of AR functioning (e.g., nuclear translocation, cofactor recruitment) have been developed. Finally, how AR interacts with other signaling pathway is being explored, and new combinations of targets to test are being proposed. Multiple compounds remain in various stages of clinical development based on targeting these resistance pathways, and hopefully, they will further the armamentarium for mCRPC. This review visits these mechanisms of resistance, how they are targeted, and remaining challenges in implementing these therapies into clinical practice among the other approved treatments.