The safety studies of the two triphenylethylene antiestrogen dings, tamoxifen and toremifene, are discussed. Tamoxifen has been shown to be a strong hepatocarcinogen in rats in several independent toxicity studies but the new antiestrogentoremifene is not a liepatocareinogen. A genotoxie mechanism is involved in tamoxifen-induced hepatocareinogenesis and the species responsible for this genotoxic effect are apparently reactive metabolites of the drug. The activation of tamoxifen to genotoxie metabolite(s) may be mediated by cytochrome P450 isoenzyines (mainly CYP3A). Tamoxifen induces high levels of DNA adducts in experimental animals in vivo and in vitro. Toremifene produces no significant amountof adducts.In long-term studies tamoxifen induces also endometrial preneoplastic lesions and some squamous cell carcinomas in the rat. Equimolar dose levels of toremifene do not produce these lesions. In humans tamoxifen increases the risk for endometrial cancers and possibly also the risk for gastrointestinal cancers