Etoposide underwent conventional Phase I testing in the 1970s. The dose-limiting toxicity in these studies was mild myelosuppression; other toxicities were infrequent. If a greater degree of myelosuppression is accepted, higher than standard doses could be given. This approach takes advantage of the steep dose-response relationship for most chemotherapeutic agents, including etoposide, as shown in early in vitro and clinical studies. Thus, etoposide was considered an ideal agent for further dose-escalation studies, given its wide range of clinical antitumor activity at standard doses, steep dose-response curve, mild bone marrow suppression, and few nonmyeloid side effects. The high-dose etoposide studies that followed used improved and more intensive hematologic supportive care, including, in some trials, autologous marrow transplantation. When etoposide was used as a single agent in these high-dose trials, mucositis, and, to a lesser degree, hepatic dysfunction were dose-limiting. The maximum tolerated dose (MTD) in this setting was 2.4 to 3.0 g/m2. Multi-agent Phase I trials with etoposide and cyclophosphamide, total body irradiation, carmustine, or carboplatin also resulted in dose-limiting mucosal toxicity, with liver and lung problems appearing more often than with high-dose etoposide alone. The toxicity and MTD can be influenced markedly by the schedule of administration. Etoposide as a continuous intravenous infusion can be given at doses of 4.2 g/m2 (with 200 mg/kg cyclophosphamide) with similar toxicity, but without marrow support. The antitumor results in the lymphomas set the stage for treatment of solid tumors, where treatment of patients with "sensitive" relapses had the best outcome. Lymphoma patients had an 80% response rate; overall, long-term (greater than 2 years) disease-free survival was approximately 40%. Germ cell tumors were also responsive, and the same pattern of sensitive relapses and improvement in responding patients was seen (50% to 75% of patients greater than 1 year). In breast cancer and small cell lung cancer (SCLC), high-dose etoposide-containing regimens were used to intensify standard therapy. The results in these settings were not quite as good (breast cancer, 30% disease-free survival at 2 years; SCLC, 10% at 2 years).