Genetic heterogeneity is a consequence of the complexity of the biology of disease. Revealing genetic heterogeneity exposes the complexity of the genotype-environment interactions that are expressed by the intervening phenotypes that link genotype with the disease endpoint. Because we have not identified the genes involved in most common diseases, studies of genetic heterogeneity have primarily focused on a statistical analysis of either the discrete endpoint or the quantitative intervening phenotypes. Rapid progress in the development of sophisticated measures of the genotype and the intervening phenotypes will enhance our ability to characterize the etiology of the chronic disease. Both statistical and molecular methods will be required to understand the impact of each of the many genes that are expected to contribute to the chronic disease burden in the population at large.