Irritability, an increased propensity to experience anger and frustration, affects up to 3.7 million children and adolescents in the U.S. Irritability and anger outbursts are among the most common reasons why children are referred to mental health services, accounting for up to 70% inpatient admissions. Occasional irritability and tantrums are normal parts of childhood. However, some children never outgrow them and remain persistently, highly irritable over development. This group of children with chronic irritability is at increased risks of having multiple psychiatric disorders, school suspensions, and social impairment. Importantly, chronic irritability in childhood is a strong predictor of adolescent and adult anxiety, depression, and suicidality. Despite the significant personal and public health impact, very little is known about the risk factors and causes of chronic irritability, limiting efforts to guide evidence-based preventions and interventions. This project—the first of its kind—addresses this critical gap by mapping out the developmental trajectories of irritability from childhood to adolescence and identifying brain markers that predict risks of chronic irritability. The sample includes 80 children ages 8–15 years (50% with clinically-impairing irritability), followed over two years. Irritability is assessed yearly at 3 timepoints (Y0, Y1, Y2) using smartphone-based measures and child-, parent-, and clinician-reports. fMRI (functional Magnetic Resonance Imaging) data are collected at the first and last timepoints (Y0 and Y2), using an established task designed to elicit frustration, given that many irritable children have low frustration tolerance. Taking a novel approach, we will use a data-driven modeling technique to map out each individual child’s irritability trajectory over time, and then apply machine learning to predict individual trajectory using fMRI data. We hypothesize that abnormal activity/connectivity in the fronto-parietal regions and striatum—brain regions supporting attention control and reward-related processes, respectively—will predict a chronic, persistent irritability trajectory. This project has great promise to identify brain markers that predict which child will follow a chronic irritability trajectory from childhood to adolescence. Results may pinpoint potential neural targets for the development and testing of novel early preventions/interventions to reduce chronic irritability, thereby preventing its negative downstream effects including depression and suicidality.