The aim of this investigation was to determine whether irritability, defined as the propensity to experience and express anger following actual or perceived provocation, is a component of the liability to alcohol and drug abuse. Sons of substance abusing fathers (n = 40) and normal fathers (n = 56) were studied when they were 10-12 years of age and followed-up 2 years later. Hierarchical regression analysis revealed that resting salivary cortisol concentration, impulsivity and family discord measured when the subjects were 10-12 years of age explained 35% of the variance on a scale measuring irritability 2 years later. At follow-up, when the boys were 12-14 years of age, it was observed that irritability scale scores and family discord were the only variables that accounted for significance variance on a scale measuring coping via alcohol and drug use. Latency and amplitude of the N1 and P3 event-related potentials of an auditory oddball task, measured at age 10-12, were not associated with drug use at age 12-14. These results indicate that family dysfunction, stress state of the child, and low behavioral self-control additively account for a significant proportion of variance on irritability scale scores 2 years later, and that this trait, in conjunction with family discord, is associated with substance use as a coping response by early adolescence.