Although the majority of patients with poor-risk germ-cell tumors (GCTs) will achieve a durable complete remission (CR) with standard first-line therapy, 20% to 30% of them will either relapse or fail to achieve an initial CR and eventually die. For this reason, the strategy of using high-dose (HD) chemotherapy with autologous stem-cell support has been investigated to improve the chances of cure attainable in the salvage setting, but at a cost of significant morbidity and mortality. Treatment using HD therapy in the first-line setting offers the promise of reducing morbidity and mortality while increasing efficacy. At Memorial Sloan-Kettering Cancer Center (MSKCC), trials were conducted to test this hypothesis. Patients at high risk of relapse following conventional therapy were identified, based on post-treatment serum marker concentrations that failed to appropriately decline by predicted half-life after several cycles of standard treatment. These patients received first-line HD treatment. Patients received a 2-drug HD regimen in one trial and an intensified 3-drug regimen in another, each with autologous bone marrow transplantation. These patients had improved overall and event-free survival rates (p = 0.001 and 0.003, respectively) compared with historical controls who underwent standard first-line treatment, with a lower incidence of treatment-related mortality than patients who received HD therapy in the salvage setting. Randomized trials are under way to prospectively verify these results.