Background: Past findings on gene-by-environment (GxE) effects on depression have been mixed, leading to a debate of the plausibility of such mechanisms and methodological considerations that warrant attention. A developmental systems perspective postulates that complex, multi-level GxE effects are likely contributors to depression. Methods: Participants from families experiencing low-income status at birth were followed over 28 years. Maltreatment was recorded prospectively using multiple means and sources. Depression was measured repeatedly using well-validated interviews in middle childhood, through adolescence, and into adulthood. Results: Findings support a GxE effect where the less efficient form of the promoter region of the serotonin transporter gene(5-HTTLPR contributes to a vulnerability to depressogenic aspects of maltreatment in childhood and adolescence. The presence of less efficient forms of the 5-HTTLPR polymorphism and maltreatment together raised risk for depression. This GxE effect was present generally and also among those who reported clinical levels of depression at only one point in time. Limitations: This study used a low-income sample which limits generalizability to other populations. Sample size and rates of different forms of depression and depression at individual developmental stages supported general analyses, but limited the sorts of specific sub-analyses that were possible. Conclusions: These findings support the plausibility of GxE effects on depression during childhood, adolescence, and early adulthood, key periods for the development of depression. Ongoing debates about the presence of GxE effects would be well served by additional work that was theoretically informed and employed prospective, longitudinal methodologies with well-validated measures of key constructs.