Etoposide (VP-16) and cisplatin are widely used in the treatment of malignancy. It is a common clinical observation that patients may initially respond to this two drug combination but later become resistant to it. Data from the CCL-159 lymphoblast cell line suggests that the emergence of resistance may be by means other than multiple drug resistance gene expression. The data suggest that chemotherapeutic failure may be mediated in part by a relatively inefficient method of drug resistance, the unstable expression of low-level drug resistance by a minority of cells. These results may help explain how patients whose malignancies are initially sensitive to VP-16/cisplatin later develop drug resistance.