Snell dwarf mice live longer than controls, and show lower age-adjusted rates of lethal neoplastic diseases. Fibroblast cells from adult dwarf mice are resistant to the lethal effects of oxidative and nonoxidative stresses, including the carcinogen methyl methanesulfonate. We now report that dwarf-derived fibroblasts are slow to enter the stage of growth arrest induced by culturing normal cells under standard culture conditions at 20% O2. Dwarf cells cultured at 20% O2 resemble control cells cultured at 3% O2 not only in their delayed growth arrest, but also in their rapid growth rates and resistance to both oxidative and nonoxidative forms of cytotoxic stress. Levels of the heat-shock protein HSP-70 respond to serum withdrawal and stress only in control cells, showing that intracellular signals are blunted in dwarf-derived cells. These data suggest a model in which stable epigenetic changes induced in skin fibroblasts by the hormonal milieu of the Snell dwarf lead to resistance to multiple forms of injury, including the oxidative damage that contributes to growth arrest in vitro and neoplasia in intact mice.