Prostate cancer is an extraordinarily heterogeneous disease with a variety of prognostic factors influential in determining ultimate patient outcomes. However, the vast majority of men harboring pathologic evidence of prostate cancer are not clinically diagnosed with this disease. Selected patients, particularly those with low clinical stage and low Gleason scores, may have extremely prolonged time until disease progression and cancer-specific death. Because of the potential for a prolonged natural history, factors, such as age and comorbidities, are often critical in evaluating clinical trial outcomes. Patients with more aggressive disease (higher clinical stage or Gleason score) have less prolonged natural histories. Careful examination of inclusion and exclusion criteria and the presence of clinical or pathologic staging are necessary for proper interpretation of clinical trials. Although surrogate endpoints, such as prostate-specific antigen and pathologic state, are commonly used to assess the effectiveness of therapeutic interventions, the relations between these surrogates and more relevant clinical endpoints have not always been well defined. Although certain endpoints are generalizable (overall survival and cancer-specific survival), clinical stage and treatments dictate the appropriateness of many other clinical trial endpoints. Both disease-related and treatment-related endpoints are important, given the propensity for various interventions to alter quality of life. Prospective randomized trials with adequate follow-up time and the assessment of clinically meaningful endpoints will offer the best opportunity to evaluate the effectiveness of various interventions used in this disease.