<p>Adolescence is a period of increased risk for the onset of depression. However, the neurobiological mechanisms underlying this vulnerability remain poorly understood despite substantial investment and efforts in this research area. In this Perspective, we review existing literature on the links between the adolescent brain and depression risk and development, and discuss methodological and conceptual challenges related to quantifying brain features and measuring depression. We highlight the importance of considering both large-scale longitudinal cohort studies and smaller focused investigator-led studies with deep phenotyping to advance our understanding of the neural basis of depression in adolescence. Emphasizing the need to embrace the developmental context and refine our methodologies, we propose several considerations to help current and future researchers advance our understanding of how the developing brain influences depression risk in today’s youth.</p>