Adenocarcinoma of the prostate is the most common cancer diagnosed in men in the United States, with approximately 189,000 new cases estimated to be diagnosed in 2002. It is believed that men with this disease pass through a series of clinical states. In the intramural program of the National Cancer Institute, we have designed clinical trials that have addressed each disease state. In addition to clinical endpoints, each trial also encompasses molecular or immunologic endpoints in an attempt to determine if our therapy is acting on its presumed target. In patients with localized disease, we are evaluating cancer vaccines in combination with radiation therapy as well as comparing this vaccine against second-line hormonal therapy in patients with rising serum prostate-specific antigen (PSA) but no radiographically measurable disease. We are also evaluating the ability of the antiangiogenesis agent thalidomide to prolong the rest period in patients with a biochemical recurrence (stage D0) that are receiving intermittent hormonal therapy. In patients with metastatic prostate cancer, we are evaluating the addition of the bisphosphonate alendronate when added to ketoconazole for impact on matrix metalloproteinase (MMP)-2 and MMP-9 as well as traditional clinical endpoints. In addition, we have 3 ongoing trials involving the chemotherapeutic agent docetaxel. One trial is examining the combination of thalidomide with docetaxel. The other 2 trials are exploring the PSA vaccine with docetaxel and the combination of docetaxel with ketoconazole. As we obtain information from these ongoing studies, we will be able to take this information and integrate it in the development of newer and more successful treatment regimens as well as look for novel agents that may help in the fight against this disease.