In this study, we show that FZD6 is the most highly expressed and frequently amplified Wnt receptor in advanced prostate cancer and provide evidence that targeting FZD6 in various aggressive subtypes of prostate cancers suppresses tumor growth, impairs DNA damage repair response, and enhances the therapeutic efficacy of cisplatin in a preclinical prostate cancer model. Here, FZD5 is linked to Familial prostate cancer.