Prostate cancer (PCa) has been the second most common cancer in men with the continuous development of the aging population, the increasing incidence and mortality rate of PCa, and complex occurrence and development mechanism of PCa. The overactivation of AR signaling pathway not only promotes the occurrence of castration-resistance PCa (CPRC), but also plays a key role in the drug resistance of PCa. Current strategies of PCa treatment are relatively limited and accompanied with several serious side-effects. Therefore, the continuous development of targeted therapy, we need to find new treatments to improve the efficacy. Numerous studies have demonstrated that the abnormal function of E3 ubiquitin ligase adaptor, speckle-type POZ protein (SPOP) has a close relationship with the occurrence and progression of PCa. Herein, this review will combine recent researches to describe the basic structure and function of SPOP, summarize the effect of SPOP on PCa, and explore the possibility of stratified treatment for PCa patients with SPOP mutations or not. For example,PCa patients with SPOP mutation can evidently enhance AR signal pathway, disrupt DNA damage response and immune response, leading to occurrence and progression of PCa. While, in the case of PCa patients with SPOP wildtype, can also occur the gene fusion, leading to imbalance of stress response protein, which may induce the occurrence and progression of PCa. Thus, it is essential that using genetic testing of patients in the early stage of treatment, which may indicate the stratified treatment for PCa patients, thus improving the prognosis of PCa efficiently.