This paper presents an integrative research-derived model to explain comorbidity among SUDs, externalizing disorders, and internalizing disorders. This hierarchical model is based on phenotypic covariance among the disorders and latent common genetic liability. At the highest level of the hierarchy, general genetically-influenced biological dispositions to negative emotionality and behavioral disinhibition each give rise to spectra of related personality traits, cognitive processes, behavioral tendencies, and psychopathology that account for the pattern of co-occurrence among mental disorders. At the lowest level of the hierarchy, disorder-specific genetic and environmental effects explain the presence of some and not other disorders associated with a given general liability. Interplay between the general liabilities and both other genes and environmental factors throughout development affect the likelihood of developing specific mental disorders.