Etoposide is an important chemotherapeutic agent in the treatment of selected patients with germ cell tumors, lymphomas, and small cell lung cancer (SCLC). Its optimal use is continuing to evolve. It is clear that schedule dependency is of critical importance. Recently, preliminary studies have suggested that a prolonged schedule of etoposide administration (21 days) may be more effective than the standard 3- to 5-day schedule. Results of several Phase II studies show chronic oral etoposide administration induces occasional responses in resistant tumors and higher-than-expected response rates in patients with germ cell tumors and SCLC. Preliminary data show nearly 90% etoposide absorption when given in a low-dose schedule (50 mg/m2/d) for 21 days. These observations indicate that etoposide may be a "new drug" when given in the chronic schedule. Further exploration of the schedule dependency of etoposide is indicated. Etoposide has recently been proven useful in selected patients with gastric, ovarian, and poorly differentiated carcinoma of unknown primary site. Several other drugs are either synergistic or additive and will be explored in combination chemotherapy. The possibility of adding topoisomerase I inhibitors and modulating etoposide's activity by inhibiting drug resistance is now within the realm of human testing.