Increasing evidence suggests that the interactions between genes and environment might play a critical role in the pathogenesis of complex diseases, such as asthma, that exhibit a heritable component but do not follow Mendel's laws. Gene- environment interactions are extremely complex and not linear, such that the same genetic variants might be associated with opposite phenotypes in different environments. This is particularly evident for innate immunity genes, which operate at the interface between the immune system and the pathogen world. This article examines gene-environment interactions by using CD14 as a model and argues that the conflicting results of epidemiologic studies on CD14C-159T result from differences in environmental conditions essential to modulate CD14 gene expression. Furthermore, on the basis of how rapidly environmental changes have affected the incidence of immune diseases, I argue that a full understanding of gene-environment interactions requires that epigenetic as well as classical genetic mechanisms be taken into account. Recent data about the effect of diet on gene methylation and the release of hidden genetic variation by impairment of heat shock protein 90–mediated buffering systems offer eloquent examples of how epigenetic mechanisms might affect gene-environment interactions.