Aggression is highly comorbid with autism spectrum disorder (ASD) and is a strong predictor of negative outcomes for patients and families. Current pharmacological options for aggression are of limited efficacy for many and can result in further morbidity. Better understanding of the neurobiology underlying aggression in ASD and novel pharmacological treatment strategies rationally derived from these mechanisms are required to solve this critical problem. Genetic, neuropathological, and animal model studies have found abnormalities of the nicotinic acetylcholine receptor (nAChR) system in brains of people with ASD, and nAChRs influence the properties of essentially all major neurotransmitter systems. The nAChR agonist nicotine reduces aggression in multiple animal models, and our preliminary data suggests its effect is via activation of the α7 receptor. CHRNA7, the gene for α7, is deleted in 15q13.3 microdeletion syndrome, which phenotypically can include ASD and aggression. This project thus hypothesizes that modulation of nAChR signaling might be a novel treatment strategy for aggression in ASD. This hypothesis will be tested by 1) identifying the neurocircuitry and pharmacology underlying nicotine’s anti-aggressive effect in mouse models of aggression and ASD, and 2) determining the efficacy of transdermal nicotine for aggression in ASD in a pilot clinical trial.