Over half this issue of The American Journal of Psychiatry is devoted to articles on the genetics of psychiatric illness. Despite extensive epidemiological evidence for the heritability of many psychiatric illnesses, controversy continues over the reliability of the major genetic findings in this field. Study designs that focus on identifying a single gene cause of disease, while successful for rarer illnesses like cystic fibrosis and muscular dystrophy, have long been abandoned in psychiatry. Most common illnesses, including psychiatric disorders, are not determined by a single gene variant but rather occur because of complex interaction between multiple genes and environmental factors. Two fundamentally different approaches, illustrated by studies in this issue, can help with this complexity. One approach is to increase the complexity of the disease models to better match the likely reality, such as studies that explicitly model gene-environment or gene-gene interactions. While conceptually straightforward, modeling this additional complexity can require larger samples to maintain adequate power. The second approach is to switch from the study of clinical illness to related traits that are hopefully controlled by simpler genetics. A caveat here is that the genetics of these alternative traits actually may be as complex as standard clinical entities. However, if a trait that is more directly controlled by a specific gene variant is identified, it can be more powerful for genetic studies. Such a trait could even be used for studies in well populations, as many healthy individuals will have a genetic variant associated with disease risk (Figure 1). Additionally, the always imprecise work in human subjects can be complemented by approaches that use animals or human cells that are grown in the laboratory and subjected to strict experimental controls. None of these designs are perfect, and concerns have been raised over each. Indeed, the review and overview article in this issue of the Journal, by Duncan and Keller (1), contributes to these concerns about reliability and is appropriately titled "A Critical Review of the First 10 Years of Candidate Gene-by-Environment Interaction Research in Psychiatry." The purpose of this editorial is not to try to resolve these controversies but rather to let our readers know what these articles, despite appropriate reservations, teach us in order to justify our publishing them for you to read.