BACKGROUND Although research on the association between temperament and psychopathology has received renewed interest, few investigations have addressed the issues of psychiatric comorbidity or the role of temperament across the life span. The present investigation employed a family study/high-risk design to examine the specificity of associations between temperamental traits and psychiatric disorders in both children and adults. METHODS The sample was composed of 244 probands and 82 children (ages 7-17) from the Yale Family Study of Comorbidity of Substance Abuse and Anxiety. Psychiatric disorders were assessed using structured diagnostic interviews administered by clinicians, and temperament was measured using the Dimensions of Temperament Survey. RESULTS In both adults and children, anxiety and depression were generally associated with low scores on adaptability and approach/withdrawal, while externalizing or substance use disorders were associated with low attention scores and higher activity. However, psychiatric comorbidity was associated with the manifestation of both clusters of temperamental traits and far greater impairment and clinical severity. Some temperamental characteristics in children also demonstrated specificity of association with parental psychiatric disorder. CONCLUSIONS This investigation was limited to the analysis of cross-sectional data and was unable to separate genetic from other familial risk factors. CONCLUSIONS The results suggest that temperament remains associated with psychopathology across the life span and may reflect diverse familial influences. Clinical intervention and prevention efforts may benefit from focusing on individuals at higher risk for psychiatric disorder through parental psychopathology or the expression of temperament problems in childhood.