Gemcitabine and etoposide have both shown single-agent activity against multiple tumor types in clinical trials, including small cell lung cancer, but have not been previously used together. Forty-four patients with small cell and non-small cell lung cancer or other tumor types were enrolled in a phase I dose-finding trial using this drug combination. Gemcitabine 1,000 mg/m2 was given intravenously on days 1, 8, and 15 of a 28-day cycle, and etoposide (dose escalated from 20 to 80 mg/m2) was given on days 8, 9, and 10. Leukopenia, thrombocytopenia, and anemia were the major toxicities noted. Objective responses were observed in five of 44 patients. The maximum tolerated dose of etoposide was determined to be 80 mg/m2. On the basis of these results, a phase II trial of gemcitabine and etoposide in patients with small cell lung cancer has been initiated. Twelve patients have been enrolled in this ongoing trial, and toxicity to date has been manageable.