Recent advances in genomics technology have led to the massive discovery of new drug targets for prostate cancer;however,none of the currently available therapeutics is curative.One of the greatest challenges is drug resistance.Combinations of therapies with distinct mechanisms of action represent a promising strategy that has received renewed attention in recent years.Combination therapies exert cancer killing functions through either concomitant targeting of multiple pro-cancer factors or more effective inhibition of a single pathway.Theoretically,the combination therapy can improve efficacy and efficiency compared with monotherapy.Although increasing numbers of drug combinations are currently being tested in clinical trials,the mechanisms by which these combinations can overcome drug resistance have yet to be fully understood.The purpose of this review is to summarize recent work on therapeutic combinations in the treatment of castration-resistant prostate cancer and discuss emerging mechanisms underlying drug resistance.In addition,we provide an overview of the current preclinical mechanistic studies on potential therapeutic combinations to overcome drug resistance.