In this paper, we provide an overview of how the maturation of specific brain regions and stress exposure during windows of vulnerability initiate a series of events that render adolescents exceptionally susceptible to the development of depression. This stress-incubation/corticolimbic development cascade provides a means of understanding why depression emerges with such force and frequency in adolescence. The development of the prefrontal cortex, hippocampus, amygdala and ventral striatum is described from a translational perspective as they relate to stress exposure, onset, pathogenesis and gender differences in depression. Adolescent depression is a serious recurrent brain-based disorder. Understanding the genesis and neurobiological basis is important in the development of more effective intervention strategies to treat or prevent the disorder.