A genetic predisposition to depression may be a potential risk factor in the development of depression. Although the neurobiological equivalent of the predisposition remains unclear, it seems as though the brain serotonin (5-HT) system plays an important mediating role. Therefore, individuals with a family history of depression (FH+) may be more likely to develop depression due to an innate vulnerability related to altered serotonergic neurotransmission in the brain. A major problem, however, is that the role of brain 5-HT in depression is complex and this serotonin-related innate vulnerability, by itself, is not sufficient enough to cause a depressive episode. In the search for additional factors, stress has received particular attention. Stressful life events influence and precede the onset of depression. Furthermore, depression is associated with stress hormone dysregulation and bidirectional interactions are thought to occur between stress-related changes in the neuroendocrine stress system and the 5-HT system. In the current review, we argue that healthy individuals with a positive family history of depression are more prone to develop depression due to a genetic 5-HT susceptibility, which deteriorates stress coping mechanisms and increases stress vulnerability.