Irritability is increasingly recognized as a significant clinical problem in youth. It is a criterion for multiple diagnoses and predicts the development of a wide range of disorders. Research on etiopathogenesis suggests that genetic and family environmental factors play a role, as do abnormalities in reward and cognitive control circuitry. However, many of these effects are age dependent. Threat-responsive self-regulatory systems and the degree to which irritability manifests as tonic or phasic influence whether irritable youth exhibit more internalizing versus externalizing outcomes.