Prostate cancer is curable only when treated at an early stage, when the tumor is still localized to the prostate gland. However, even in apparent cases of clinically localized disease, unsuspected extracapsular disease may significantly increase the risk of primary treatment failure. This risk is especially high if the patient has > or =1 of the following risk factors: a serum prostate-specific antigen level of >20 ng/ml, a Gleason score of >7, locally advanced disease (clinical stage T3/T4), and extensive disease on prostate biopsy. Various regimens of neoadjuvant hormonal therapy, chemotherapy, or both have produced mixed results and, in general, have not significantly influenced the rate of disease relapse (as defined by prostate-specific antigen level) in high-risk patients with localized prostate cancer. In addition, anti-angiogenic agents, gene therapy, molecular targeting agents, and other promising new therapies have been investigated in a neoadjuvant setting with limited results. Therefore, this patient population continues to pose a therapeutic dilemma for physicians.