During the past two decades, dramatic strides have been made in the treatment of metastatic testicular cancer. In the early 1970s, cisplatin, vinblastine, and bleomycin (PVB) produced durable complete remissions (CR) in approximately 70% of treated patients. In the early 1980s, etoposide emerged as the only drug with single-agent activity in cisplatin-refractory patients. Based on preclinical data demonstrating synergy of cisplatin plus etoposide, the two-drug combination proved to be a useful salvage therapy, curing approximately 25% of such patients. Further evaluation of etoposide as part of initial therapy by the Southeastern Cancer Study Group (SECSG) compared PVB with bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with metastatic germ cell tumors. Not only did BEP have significantly less toxicity, it proved to be superior to PBV in patients with advanced disease. Varying the dose and schedule of etoposide also may provide patients with potentially useful avenues of treatment. High-dose etoposide plus carboplatin in drug-refractory patients has produced durable CR in a cohort of treated patients; it is currently being evaluated as part of initial salvage therapy. The schedule dependency of etoposide in small cell lung cancer led us to evaluate daily oral administration of etoposide in patients refractory to previous etoposide therapy; objective response rates of approximately 15% to 25% were observed. In summary, etoposide remains an integral part of the treatment regimen for testis cancer. However, the incorporation of innovative dose and schedule combinations for etoposide may further improve its therapeutic index for this disease.