Adenocarcinoma of the prostate is a common malignancy affecting one in nine men, with six of every 10 cases identified in men older than 66 years, and more adversely affects African American males. It remains less common in men under the age of 40. The age adjusted incidence is increasing with the application of prostate specific antigen (PSA) as a biomarker. PSA helps identifying the disease at an early stage, which is treatable and curable with traditional therapies. However, a significant percentage of men present with high Gleason grade and advanced disease, with lower PSA, and younger age at presentation. These patients can have a compromised outcome. Once again, we are evaluating patients under the age of 50 with advanced disease due in part to inconsistent application of clinical screening. More effort is needed for high-risk patients to provide timely, meaningful intervention and effective therapy. In this chapter, we review the status of therapy for standard and high-risk patients, and strategies for translational science for patients at risk of compromised outcome and treatment failure.