Major Depressive Disorder (MDD) is a prevalent illness and is projected to be the leading cause of disability by 2030. While the prevalence of depression is low during childhood, the cumulative probability of MDD rises dramatically from 5% in early adolescence to 20% by young adulthood. Importantly, the onset of MDD during adolescence adversely affects the course and prognosis of the disorder: early-onset MDD is associated with longer, more severe, and recurring depressive episodes that are often refractory to treatment. Despite the clear role that developmental processes play in the emergence of depression during adolescence, we know little about neurobiological markers that predict the course of depression. We must bridge this gap to effectively pursue brain-based personalized treatments.