From chimney sweeps to oncogenes: the quest for the causes of cancer. Over the past 200 years, a bewildering array of chemical, physical, and viral agents has been identified that can cause cancer, but the mechanisms involved are only now becoming clear. In the leukemias and lymphomas, it appears that the activation of cellular oncogenes is important. The genes involved are present in all normal cells and are often associated with cell growth and regulation. When activated, they act in a dominant fashion to cause a cell to express the malignant phenotype. There is increasing evidence that in solid tumors, a more important mechanism may be the loss of a suppressor gene. The classic example is retinoblastoma, in which the retinoblastoma gene has been cloned and is also found to be associated with several other common cancers including sarcomas and small cell lung cancer. It is likely to be one of a family of such genes. It may well be that the activation of one or more oncogenes or the loss of one or more suppressor genes, or both, is required for a tumor to progress from initiation through promotion to a metastasizing malignancy. 