For the past several decades, the phenomenon of depression largely has been defined, classified, and thus assessed and analyzed, according to criteria based on the Diagnostic and Statistical Manual (now DSM5). A substantial body of knowledge on epidemiology, course, risk factors, correlates, consequences, assessment, and intervention for youth depression is based on this classical nosological approach to conceptualizing depression. Yet, recent structural and classification approaches, such as latent dimensional bifactor models (e.g., P factor model; Caspi et al., 2014) and hierarchical organizations (e.g., HiTOP; Kotov et al., 2017), have been proposed and supported as alternative options to characterize features of depression. This paper considers conceptualizations of depression among youth with a particular focus on validity: how important clinical outcomes and risks (genetic, neural, temperament, early pubertal timing, stress, and cognitive) relate to depression when ascertained via traditional DSM-defined depression versus more recent latent dimensional model approaches. The construct validity of depression, in terms of associations within respective nomological networks, varies by depression conceptualization. Clinical scientists and applied practitioners need to clearly think through the nature of what depression is and how the latent construct is conceptualized and measured. Conclusions reached for research, teaching, and evidence-based clinical work are affected and may not be the same across different conceptual and nosological organizational schemes.