Despite abundant research demonstrating the magnitude of comorbidity and its importance in understanding childhood psychopathology, there has been limited empirical research designed to examine the nature and causes of comorbidity among youth. This article reviews the current literature on the magnitude and mechanisms of depressive comorbidity and presents data to exemplify the application of high-risk and longitudinal study designs to investigate patterns and explanations for comorbidity. A prospective family study of offspring at high and low risk for the development of anxiety was used to examine the specificity of familial comorbidity of depression and anxiety and the longitudinal stability of "pure" and comorbid disorders over an 8-year period. Findings suggest some specificity of familial expression, as well as longitudinal specificity, of depression and anxiety. The onset of depression follows the onset of most anxiety subtypes, suggesting the sequential nature of depressive comorbidity. Evaluation of mechanisms for comorbidity is important for the identification of homogeneous syndrome categories that will inform research designed to gain understanding of the pathogenesis of mood or anxiety disorders.