Despite the substantial heritability of nearly all psychological traits, it has been difficult to identify specific genetic variants that account for more than a tiny percentage of genetic variance in phenotypes. Common explanations for this “missing heritability” include massive polygenicity, rare variants, epigenetics, epistasis, and gene–environment interactions. Gene–trait (G × T) interaction is another concept useful for understanding the lack of obvious genetic main effects. Both genes and environments are distal contributors to human behavior, but the brain is the proximal driver of behavior. The effect of any single genetic variant is dependent on the configuration of the brain in which it is expressed. One method to begin studying how single genes interact with variations in the rest of the brain is to investigate G × T interactions. A psychological trait reflects a characteristic pattern of psychological function (and, therefore, of brain function), which has its origin in the cumulative effects of both the genome and the environment. A trait therefore describes variation in the broad organismic context in which any single gene operates. We describe the nature and significance of G × T interactions for understanding psychopathology and normal trait variation, which are illustrated with empirical examples.