Etoposide, despite extensive use in other malignancies, has played a minor role in the treatment of patients with breast cancer. Single-agent trials in which etoposide is administered to heavily pretreated patients with metastatic breast cancer have demonstrated a low overall response rate (6.6% of 383 patients), with no convincing evidence for either schedule dependence or a relationship between dose intensity and response. The sole single-agent trial in previously untreated patients suggested that the drug has an approximately 15% response rate in untreated patients. Combination therapy trials in which etoposide has been combined with either cyclophosphamide, doxorubicin, or cisplatin have not yet convincingly demonstrated superiority over any of these drugs as single agents, although cisplatin plus etoposide appears to be superior to either agent alone. In vitro studies suggest that pretreating hormone-sensitive breast cancer cells with estradiol may increase their sensitivity to etoposide-induced DNA cleavage. This may represent a future direction in the use of etoposide in breast cancer. Currently, however, the use of etoposide in breast cancer should be considered investigational.