A symposium of this title was presented at the 37th Annual Meeting of the Society of Toxicology held in Seattle, Washington during March of 1998. The symposium focused on heritable variations in metabolism, DNA replication, and DNA repair that may predispose humans to environmental diseases. Human metabolic, replication, and repair enzymes function in protective roles. Metabolic enzymes are protective because they detoxify a stream of chemicals to which the body is exposed. Replication and repair enzymes are also protective; they function to maintain the integrity of the human genome. Polymorphisms in the genes that code for some of these enzymes are known to give rise to variations in their protective functions. For example, functional polymorphisms of the N-acetyltransferases, paraoxonases, and microsomal epoxide hydrolases vary in their capacity to metabolize environmental chemicals. Specific isoforms of the N-acetyltransferases and microsomal epoxide hydrolases are increasingly associated with incidences of cancer attributable to exposure to these chemicals. Thus, maintenance of cellular-growth homeostasis, normally and in the face of environmental challenge, is dependent on an inherited assortment of metabolic isoforms. Since replication and repair are also protective cellular functions, and since mutations in genes that code for these functions are associated with tumorigenesis, one can reasonably speculate that common functional polymorphisms of replication and repair enzymes may also impart susceptibility to environmental disease.