Recent attention is focused on understanding the genetic basis for individual susceptibility to the development of chronic disease. An emphasis is concentrated on establishing an association between inheritance of polymorphic chemical metabolizing genes and development of environmental cancer (e.g., lung cancer among cigarette smokers). The early reports of such associations have been very encouraging. However, some reported positive associations were not substantiated in subsequent studies using larger sample sizes and different ethnic populations. In this review, some confounding factors that contribute to the discrepancies are presented (e.g., ethnic-dependent distribution of variant gene alleles, differential expression of metabolizing genes, and inadequate study design). It is possible that the precision of the association can be improved if the mentioned investigations are complemented with concurrent studies of biological activities/effects. The usefulness of integrating metabolic susceptibility with biomarker measurement for understanding the development of lung cancers is presented. The importance of using adequate sample size and experimental design is emphasized. Development of a reliable approach for prediction of environmental disease not only will provide fundamental information regarding the genetic basis of human disease but will be useful for reducing disease burden in the population and for advancing patient care. Environ. Mol. Mutagen. 37:215-225, 2001. Β© 2001 Wiley-Liss, Inc.