Objective: While some irritability in children is normal, severe chronic irritability may lead to highly disruptive behavior with adverse effects on the family, the school, and the child's peer relations. Research has suggested that severe chronic (non-episodic) irritability may be different than severe episodic irritability, not just in the behavioral phonotype but also in the neuropathology. It may be tempting to treat clinically significant severe chronic irritability (e.g., Severe Mood Dysregulation, Disruptive Mood Dysregulation Disorder [DMDD]) with medications and therapies used for severe episodic irritability (e.g.; Bipolar Disorder, Intermittent Explosive Disorder), but for interventions to be effective they must target the underlying neuropathology that drives the irritability. This presentation will review the limited evidence regarding the neuropathology of severe chronic irritability in youth, as described by DMDD (the new diagnostic category in DSM-5) and present a preliminary hypothesis based on this evidence. The presentation will describe also preliminary treatment implications of this hypothesis, such as medication, psychotherapy, and parent training. In the absence of prospective research, using randomized controlled trials, retrospective studies in support of this hypothesis will also be reviewed.