The study of the genetics of complex human disease has met with limited success. Many findings with candidate genes fail to replicate despite seemingly overwhelming physiological data implicating the genes. In contrast, animal model studies of the same genes and disease models usually have more consistent results. We propose that one important reason for this is the ability to control genetic background in animal studies. The fact that controlling genetic background can produce more consistent results suggests that the failure to replicate human findings in the same diseases is due to variation in interacting genes. Hence, the contrasting nature of the findings from the different study designs indicates the importance of non‐additive genetic effects on human disease. We discuss these issues and some methodological approaches that can detect multilocus effects, using hypertension as a model disease. This article contains supplementary material, which may be viewed at the BioEssays website at http://www.interscience.wiley.com/jpages/0265‐9247/suppmat/index.html. BioEssays 26:170–179, 2004. © 2004 Wiley Periodicals, Inc.