Prostate cancer is the most common form of cancer in men with highly variable clinical response, reflecting the heterogeneity of the disease. Indeed, several recent studies have highlighted the molecular and genetic diversity among prostate cancers including a wide range of androgen receptor (AR) activity, which is the central axis of the disease. Interestingly AR activity did not show high correlation with AR mRNA or protein level in tumors, implicating other factors in this phenomenon. Given that AR is the central therapeutic target in this disease, we asked if AR targeted therapy have different impact on tumors with differential AR activity. Our data provided evidence that prostate cancer cells with varying AR activities have different molecular characteristics and the tumors with high AR activity are more resistant to AR-targeted therapy. We also identifiedGREB1 as a potential new AR cofactor that enhances AR activity and Enzalutamide resistance in tumors with high AR activity. Further understanding of the function of GREB1 will provide novel insights into the development of effective therapeutic approaches to treat Enzalutamide resistant prostate cancer.