Facile gene amplification is one aspect of the genetic instability associated with transformed cells. Amplification of oncogenes and proto-oncogenes contributes to carcinogenesis and tumor progression. Gene amplification is also a common basis for resistance to anticancer drugs. The observation that low level cytotoxic stress can cause rapid loss of amplified genes from cultured cell populations suggests that gene amplification may be a potential target for cancer chemotherapy. Drug-induced loss of amplified genes is seen with a wide variety of extrachromosomally amplified genes, including drug resistance genes and proto-oncogenes. A number of drugs and differentiating agents have been reported to cause rapid loss of unstably amplified genes. An effect on amplified genes or cells carrying amplified genes may contribute to the selective action of drugs presently used for cancer chemotherapy. A better understanding of drug-induced amplified gene loss may lead to new strategies for cancer treatment.