Continued research in the treatment of castration-resistant prostate cancer (CRPC) has allowed for a clearer understanding of this disease entity and further treatment advances. In a study recently published by Beer et al. in the New England Journal of Medicine, another advance to treatment was demonstrated for the androgen receptor (AR) signaling inhibitor, enzalutamide, in patients with chemotherapy-naïve metastatic CRPC. Although a large majority of patients responded favorably to enzalutamide in the prechemotherapy setting, a small but significant proportion of patients demonstrated no meaningful benefit to this agent. This highlights an important concept in the understanding of this disease: inherent and acquired resistance to AR-targeting therapies.