Adolescence is a period of rapid neural and behavioral development that often precipitates substance use, substance use disorders (SUDs), and other psychopathology. While externalizing disorders have been closely linked to SUD epidemiologically, the comorbidity of internalizing disorders and SUD is less well understood. Neuroimaging studies can be used to measure structural and functional developments in the brain that mediate the relationship between psychopathology and SUD in adolescence. Externalizing disorders and SUD are both associated with structural and functional changes in the basal ganglia and prefrontal cortex in adolescence. The neural mechanisms underlying internalizing disorders and SUD are less clear, but evidence points to involvement of the amygdala and prefrontal cortex. We also highlight independent contributions of SUD, which may vary in certain ways by the substances assessed. A deeper understanding of the neural basis of the relationship between psychopathology and SUD will allow for more informed interventions in this critical developmental stage. •Externalizing disorders and comorbid SUD in adolescence may involve the basal ganglia and prefrontal cortex.•Internalizing disorders and comorbid SUD in adolescence may involve the amygdala and prefrontal cortex.•SUD is associated with frontal cortical thinning in adolescence.