The effects of bleomycin upon epithelial DNA synthesis have been evaluated in a keratinizing tissue culture line and following topical application on intact mouse epidermis. In both models, bleomycin inhibited epithelial DNA synthesis after prolonged exposure of the tissue to large doses of the polypeptide antibiotic. The effect is probably limited by the penetration of bleomycin through epithelial cell membranes. Inhibition of epidermal DNA synthesis was also observed in non-treated animals subjected to restraint and/or partial starvation. These conditions, which are commonly associated with studies of topical therapeutic agents, must, therefore, be carefully controlled.