Patients with androgen-independent prostate cancer demonstrate progression of disease, despite chemical or surgical castration, and have a poor prognosis. Cancer progression may be manifest as an asymptomatic increase in serum prostate-specific antigen (PSA) or may be accompanied by symptomatic and/or radiographic evidence of tumor growth. Observation remains a reasonable choice for asymptomatic patients. However, many patients remain anxious about withholding further treatment and, although studies have not demonstrated a survival benefit with second-line hormonal therapy, it may be appropriate to consider these therapies. In patients who have radiographic and/or symptomatic progression, the use of second-line hormonal therapy is more easily justified. Treatment options include: (1) secondary use of antiandrogens (eg, high-dose bicalutamide), (2) therapies targeted against adrenal steroid synthesis (eg, ketoconazole, aminoglutethimide, and corticosteroids), and (3) estrogenic therapies (eg, diethylstilbestrol). Symptomatic improvement and PSA-level decreases of ≥50% have been reported in approximately 20% to 80% of patients with androgen-independent prostate cancer who receive such second-line hormone therapies, with a typical response duration of 2 to 6 months. Toxicity is generally mild for these oral therapies, although serious side effects, including adrenal insufficiency, liver toxicity, and thrombosis, may occur. In conclusion, secondary hormonal therapies have a significant role in the treatment of patients with androgen-independent prostate cancer. Further research is needed to understand their optimal use.