Gene-environment (G × E) interaction research is an emerging area in psychiatry, with the number of G × E studies growing rapidly in the past two decades. This article aims to give a comprehensive introduction to the field, with an emphasis on central theoretical and practical problems that are worth considering before conducting a G × E interaction study. On the theoretical side, we discuss two fundamental, but controversial questions about (1) the validity of statistical models for biological interaction and (2) the utility of G × E research for psychiatric genetics. On the practical side, we focus on study characteristics that potentially influence the outcome of G × E interaction studies and discuss strengths and pitfalls of different study designs, including recent approaches like Genome-Environment Wide Interaction Studies (GEWIS). Finally, we discuss recent developments in G × E interaction research on the most heavily investigated example in psychiatric genetics, the interaction between a serotonin transporter gene promoter variant (5-HTTLPR) and stress on depression.