The variation in individual responses to exogenous agents has been shown to be exceptionally wide. It is because of this large diversity of responsiveness that risk factors to environmentally induced diseases have been difficult to pinpoint, particularly at low exposure levels. Opportunities now exist for studies of host factors in environmentally induced cancer or other diseases in which an environmental component can be presumed. Many of the studies have shown an elevated disease proneness for individuals carrying the potential at-risk alleles of metabolic genes, but a number of controversial results have also been reported. One possible explanation for the divergent findings is lack of knowledge of the other potentially relevant genotypes for a given exposure. This paper gives an overview of the published data on combinations of metabolic genotypes in relation to individual susceptibility to environmental toxicants.