Smokers have frequently been heard to defend their habit by recounting anecdotes about relatives or friends who have smoked heavily for many years without developing cancer. While individuals who have survived many years of repeated mutagen exposure are probably very rare, their existence suggests that some people are intrinsically resistant to the effects of carcinogens, probably because of their genetic background. This interpretation is supported by studies on mouse strains that are highly resistant to the development of tumours induced by treatment with exogenous carcinogens. In this review we discuss the advantages of the mouse as a model system for the isolation of cancer-resistance genes that have potentially important uses in diagnostics, prevention and tumour therapy.