The impact of genetic factors on the pathogenesis of allergy and asthma is currently an area of intense investigation. Although epidemiological studies find more and more genes that are likely to contribute to allergic inflammation, functional studies of the mechanisms that link genetic variation with dysregulation of gene expression and function are hindered by the high frequency of natural variation. The interplay between genes and environment adds another layer of complexity to the determination of allergic phenotypes. The complexity emerging from these studies warrants novel experimental strategies and bolder conceptual paradigms.