Background: Family history of mood disorders and stressful life events are both established risk factors for childhood depression. However, the role of mediators in risk trajectories, which are potential targets for intervention, remains understudied. To date, there have been no investigations of mediating relationships between risk factors and very early onset depression, a developmental period during which intervention may be more effective. The current study used regression analyses to examine the relationships between family history of mood disorders and stressful life events as risk factors for depression in a preschool sample. Method: Preschoolers 3.0 to 5.6 years of age participated in a comprehensive mental health assessment. Caregivers were interviewed about their children using a structured diagnostic measure to derive DSM-IV major depressive disorder (MDD) diagnoses and dimensional depression severity scores. Family history of psychiatric disorders and preschoolers' stressful life events was obtained. Results: Both family history and stressful life events predicted depression severity scores 6 months later. Analyses examining the influence of family history of mood disorders and stressful life events on preschoolers' depression severity demonstrated that stressful life events mediated the relationship between family history and preschoolers' depression. Conclusions: Findings outline the key role of exposure to early stressful life events as a mediator of familial mood disorder risk in preschool onset depression. This finding in a preschool sample provides support for the hypothesis that psychosocial factors may have increased importance as mediators of risk in younger age groups. Findings suggest that psychosocial factors should be considered key targets for early intervention in depression.