Fish from urban and industrialized estuaries are exposed among the highest levels of contaminants of any vertebrate populations. As a result, they serve as especially relevant models for determining the toxic effects and mechanisms through which environmental toxicants work. In controlled laboratory experiments, fish from highly contaminated locales sometimes exhibit resistance to contaminant-induced toxicity. Resistance may be due to genetic adaptation or physiological acclimations. Distinguishing between these possibilities is important in predicting the persistence of resistance and its potential costs to affected populations and communities. Along the Atlantic coast of North America, populations of two estuarine species, Atlantic killifish (mummichog) Fundulus heteroclitus and Atlantic tomcod Microgadus tomcod, exhibit phenotypes that are resistant to aromatic hydrocarbon (AH) contaminants, including polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polycyclic aromatic hydrocarbons (PAHs). Populations of these species exhibit resistance to AH-induced lethality, early life-stage toxicities, and expression of cytochrome P4501A (CYP1A). However, some differences among populations in the occurrence and type (genetic or physiological) of AH-resistant phenotypes have been observed. In some instances, resistance was obviously genetic and resulted in its transmission to at least the F2 generation, in others, resistance had a physiological or yet to be identified epigenetic basis. In some cases, resistance was observed for all AH compounds tested, in others, it was seen only for halogenated AHs. As toxic responses to AHs are believed to be mediated by the aryl hydrocarbon receptor pathway (AHR), several studies compared the structure and expression of AHR pathway molecules between resistant and sensitive fish populations. However, no obvious differences in these molecular parameters were observed between resistant and sensitive populations at the transcriptional level. Further studies at the protein level are recommended to further evaluate the role of the AHR pathway in conferring resistance. Open-ended microarray and proteomic approaches may provide additional resolution in determining the molecular mechanisms of resistance. Also, studies that evaluate the prevalence and ecosystem cost of resistance are needed.