Gene–environment interplay is a general term that covers several divergent concepts with different meanings and different implications. In this review, we evaluate research evidence on four varieties of gene–environment interplay. First, we consider epigenetic mechanisms by which environmental influences alter the effects of genes. Second, we focus on variations in heritability according to environmental circumstances. Third, we discuss what is known about gene–environment correlations. Finally, we assess concepts and findings on the interaction between specific identified genes and specific measured environmental risks. In order to provide an understanding of what may be involved in gene–environment interplay, we begin our presentation with a brief historical review of prevailing views about the role of genetic and environmental factors in the causation of mental disorders, and we provide a simplified account of some of the key features of how genes ‘work’.