The old classification of depression as reactive and endogenous, which are still observed in clinical practice, both cannot be accommodated under the current rubric of major depression. This is because psychiatric nosology under the Diagnostic and Statistical Manual of Mental Disorders (DSM) and its latest fifth edition (DSM-V) is still descriptive and not etiologic. The aim of this review was to revisit reactive and endogenous categories of depression from the perspective of today's understanding of etiological pathways. From an epigenetic perspective, the old dichotomy of reactive versus endogenous is interrelated through the impact of the environment (e.g., stress). This includes familial or prenatal depression, where the environmental impact is before birth, or childhood depression, where the early life stress is the precipitating factor to genetic susceptibility. In conclusion, searching for both environmental impact (e.g., stressors) and genetic predispositions in depression, even at a clinical level, could help clinicians with better therapeutic decisions.