Polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) are compounds whose physical/chemical properties led to their widespread commercial use. Although their production has been banned or severely limited in most countries since the 1970s, the persistence and stability of these compounds have resulted in a worldwide distribution, especially of PCBs. PBB contamination is limited principally to the state of Michigan, where a series of tragic errors eventually resulted in the accumulation of residues in livestock and the general human population. Long-term exposure to PCBs and PBBs in animals has been associated with the induction of neoplastic nodules in the liver and in some cases hepatocellular carcinoma. This review discusses the role of PCBs and PBBs in the process of carcinogenesis. The mutagenicity/genotoxicity of these compounds, as well as their initiation/promotion potential is discussed. The epidemiology of PCB and PBB exposure is reported along with an estimation of the risk of cancer to humans. Finally, possible molecular mechanisms of action are suggested for polyhalogenated biphenyls in cancer development.