A number of studies have shown that the presence of short (S), as opposed to long (L), allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) is associated with a higher risk for depression following exposure to stressful life events. However, many other studies failed to confirm this association. One reason for this inconsistency might be the fact that the interaction of the 5-HTTLPR polymorphism with stress may relate not to depression per se, but rather to adaptive or maladaptive emotion regulation strategies. Here we show that individuals homozygous for the long allele respond to stressful events by reappraising their emotional meaning, which may hamper the harmful effect of stress on mental health. In S genotype carriers, on the other hand, stress triggers the appearance of intrusive thoughts and vain attempts to suppress them, which in this group acts as a mediator between stress and depressive symptoms. These findings are in line with neuroimaging studies showing that 5-HTTLPR polymorphism has an effect on the connectivity among key areas involved in emotion regulation.