Resistance to carcinogenesis in the rat is both strain- and tissue-specific. The phenotypic characteristics of resistance in the mammary gland, liver and peripheral nervous system (PNS) are strikingly similar. In all three tissues, initiation is intact with subsequent formation of preneoplastic cells and lesions. In the mammary gland and PNS, activation of the Ha-ras and neu proto-oncogenes, respectively, takes place. A number of different modifier genes are involved in resistance, many of which appear to be tissue-specific in their action with no overlap between strains. A single resistance phenotype, however, involving the formation, growth and subsequent loss of preneoplastic lesions is common to all three tissues of resistant strains. In the PNS, there is evidence that preneoplastic cells are eliminated by apoptosis or immunosurveillance. In the mammary gland and liver, the immune system is not involved in the loss of preneoplastic lesions and there are no clear differences between susceptible and resistant strains in the kinetics of proliferation and apoptosis of preneoplastic cells. The evidence to date favors a mechanism in which preneoplastic cells from these tissues undergo a process of remodeling/redifferentiation to yield cells with a normal phenotype. Identification of human homologues of rodent tumor-modifier genes will result in a better understanding of cancer development and potentially provide new strategies for prevention and therapy.