Current treatments for patients with prostate cancer generally are successful. However, in a subset of patients identified with high-risk prostate cancer, disease will likely recur after local therapy. The optimal treatment plan for these patients has not been determined. The search for an effective treatment for this subset of prostate cancer patients has focused on multimodality therapy. Although chemotherapy has proven clinical and survival benefits for patients with metastatic disease, its role in earlier stages of the disease is being investigated. Current data have demonstrated that neoadjuvant or adjuvant chemotherapy is relatively safe and feasible. There also is emerging evidence of clinical benefit when early chemotherapy is combined with local treatments. Further investigation through prospective, randomized trials is critical to define the precise role of this modality in high-risk populations.