The example of complex interactions between environmental exposures and polymorphisms in the CD14 gene in predisposing for allergy-related conditions offers a good indication of the complexity of the mechanisms that determine susceptibility to these conditions. Contrary to what has been the rule for monogenic diseases, the association between genetic variations and polygenic conditions such as asthma and allergies may not always be unidirectional; that is, not always will the same alleles be associated with the conditions under study. Concepts of penetrance of genetic variations that ignore these nonlinear influences (which may affect gene-gene and gene-environment interactions) may hinder a better understanding of mechanisms of disease involved, and therefore may delay the development of preventive strategies for these common conditions. Discrepancies between well-designed genetic studies of asthma and allergies, therefore, may be suggesting something fundamental about how these diseases develop and how it will be possible to abolish them in the future.