The current project aimed to determine whether a recently developed explanatory model for comorbidity patterns--labeled the Hierarchical-Spectrum Model (HSM)--could serve as a useful organizing framework for research on psychopathology. The HSM accounts for the high co-occurrence of depressive and anxiety disorders by representing them as facets of an overarching Internalizing dimension; likewise, the substance use and antisocial behavior disorders are represented as facets of an Externalizing dimension. In latent variable modeling terms, the HSM parses the shared and unique variance of disorders into transdiagnostic latent factors (i.e., Internalizing and Externalizing dimensions) and diagnosis-specific residuals, respectively. This project integrated the HSM quantitative structure with prominent genetic and psychosocial theories of psychopathology. Results from Study 1 demonstrated that the relationship of early environmental adversity with psychopathology in young adulthood is partly mediated by the transdiagnostic dimensions. At the same time, early adversity was associated with several residual variances of the HSM, signaling the presence of diagnosis-specific pathways from early adversity to mental disorder. Study 2 conceptualized the stress generation hypothesis, which posits that people with a history of depression, relative to their never-depressed counterparts, experience more stressful life events dependent at least in part on their own behavior, through the lens of the HSM. Results revealed stress generating effects of the Internalizing and Externalizing dimensions, suggesting that the stress generation phenomenon is not specific to any one diagnostic category. Yet, the diagnosis-specific components of major depression and dysthymia also contributed to stress generation over and above the effects of the transdiagnostic dimensions, suggesting there is some pathology unique to depression that confers vulnerability to stress exposure. In Study 3, a daily diary methodology was used to examine day-to-day fluctuations of HSM symptoms. Consistent with expectations, elevated daily stress levels predicted increases in both Internalizing and Externalizing symptoms. Further, a widely studied polymorphism in the serotonin transporter gene (5-HTTLPR) moderated the relationship between daily stress and Internalizing, but not Externalizing, symptoms. Together, the current findings suggest that the HSM has the potential to be a useful framework for research, treatment, and classification in clinical psychology.