Irritability, defined as an increased propensity to exhibit increased anger relative to oneâs peers, is a common clinical problem in youth. Irritability can be conceptualized as aberrant responses to frustration (where frustration is the emotional response to blocked goal attainment) and/or aberrant âapproachâ responses to threat. Irritable youth show hyper-reactivity to threat mediated by dysfunction in amygdala, medial prefrontal cortex, ACC, insula, striatum, and association cortex. Irritable youth also show abnormalities in reward learning, cognitive control, and responses to frustration. These abnormalities are mediated by circuitry that includes the inferior frontal gyrus, striatum, anterior cingulate and parietal cortices. Effective treatments for irritability are lacking; pathophysiological research can lead to more precisely targeted interventions.