Diethylstilboesterol (DES) is one of the few substances for which a clear association with carcinogenicity has been established in man. Nevertheless, it is still widely used, mainly as a cheap oestrogen to increase the slaughter weight of beef, but in spite of this it is not known if residues in the meat or metabolites excreted by the cattle are hazardous to man. It is also unknown whether there is a threshold dose below which DES is harmless. A threshold might be expected if a hormonal mechanism of carcinogensis rather than metabolic activation to an electrophically reactive species operats. This possibility was supported by the observations that DES, in contrast to most other carcinogens, failed to induce mutations in the Salmonella/microsome test or malignant transformations of eukaryotic cells in culture. It is also disturbing that DES, one of the few known human carcinogens was negative in these two most widely used short-term tests introduced as fast early-earning system for potential carcinogens. We now report that DES is positive in sister chromatid exchange (SCE) induction, a short-term test for which a high correlation with the carcinogenicity of the compounds tested has been observed. Moreover, we show that metabolic activation was involved. Two different pathways leading to metabolites much more active in SCE induction than DES itself ('proximate agents') were established.