Prostate cancer patients with clinical stage T3 disease, biopsy Gleason scores of 8 to 10, or serum prostate-specific antigen levels greater than 20 ng/mL are at high risk of recurrence despite local therapy. Although hormonal therapy has palliative benefit for the majority of patients with metastatic disease, randomized trials have not demonstrated a survival benefit for its administration prior to surgery for locally advanced disease. Historically, chemotherapy has been felt to have little activity in hormone-refractory prostate cancer, but new evidence may refute this belief. Ongoing clinical trials are now investigating the use of chemotherapy in the neoadjuvant setting. We review the recent literature regarding the use of neoadjuvant hormonal manipulation, chemotherapy, and promising new molecular targeted agents in patients with high-risk localized prostate cancer.