Gene-environmental interaction (G x E) between a common functional polymorphism in the promoter region of the serotonin transporter gene (5-HTT) and environmental adversity on the onset of depression in humans has been found in fifteen independent studies. It is supported by evidence from animal experiments, pharmacological challenge and neuroimaging investigations. However, negative findings have been reported in two large samples. We explore reasons for the inconsistencies and suggest means to their resolution. Sample age and gender composition emerge as important factors. While the G x E has been consistently detected in young adult samples, there are contradictory findings in adolescent boys and elderly people. The method of assessment of environmental adversity is also important with detailed interview-based approaches being associated with positive G x E findings. Unresolved issues in the definition of the genotype include the dominance of alleles and influence of other polymorphisms, both in 5-HTT and other genes. Assessment of multiple adverse outcomes, including depression, substance use and self-destructive behaviour is needed to clarify the generalisability of the G x E pathogenic mechanisms. Biological and behavioural intermediate phenotypes are yet to be exploited to understand the mechanisms underlying the G x E.