Populations of marine, estuarine, and freshwater fish from highly urban and industrialized sites in North America often exhibit elevated prevalences of neoplastic, preneoplastic, and nonneoplastic hepatic lesions, and sometimes epidermal neoplasms compared to conspecifics from more pristine reference locales. Positive statistical associations with environmental concentrations of PAHs and other xenobiotics and experimental laboratory studies suggest a chemical etiology to these epizootics. Studies have investigated the expression of carcinogenically relevant genes, the extent of overall DNA damage, somatic cell mutations, germ line polymorphisms, and overall levels of genetic diversity in fish from these populations and other polluted sites. In general, elevated levels of cytochrome P4501A expression have been found in fish from contaminated locales; however, inhibition of gene induction has been seen in hepatic lesions and in normal tissue in fish from the most contaminated sites, perhaps due to genetic adaptation or physiological acclimation. Levels of bulky hepatic DNA adducts, as detected by 32P-postlabeling, are almost always elevated in fish from populations that are exposed to highly contaminated environments. However, levels of DNA adducts were not always predictive of the vulnerability to neoplasia of populations and species from polluted sites. Elevated levels of oxygen radical-induced DNA damage have been observed in hepatic tumors, preneoplastic lesions, and normal livers in a single species of flatfish from contaminated sites; however, the prevalences of these alterations in other species and at other polluted sites has yet to be evaluated. Frequent alterations in the K-ras oncogene have been reported in hepatic neoplasms in several species from highly contaminated sites and also in embryos that were experimentally exposed to oil-contaminated sediments. Studies also suggest that heritable germ line polymorphisms, altered allelic frequencies, and reductions in overall genetic diversity may have occurred in some highly impacted populations; however, the origin and functional significance of altered allelic frequencies have largely yet to be evaluated. In summary, feral fish appear particularly sensitive to DNA alterations from xenobiotics, perhaps due to their unusually high levels of exposure, relatively inefficient DNA repair, and the high frequency of polyploidy in some taxa and provide excellent models to explore the relationships between xenobiotic exposure and altered gene structure and expression.