Paranoid ideation—the mistaken belief that intentional harm is likely to occur—spans a continuum, from mild suspicion to persecutory delusions. Among patients with schizophrenia and other psychosis disorders, elevated levels of paranoia are common, debilitating, and challenging to treat. The cues (public environments, strangers) and processes (anxiety) that promote paranoia have grown increasingly clear, but the brain bases of these pathways are unknown, thwarting the development of mechanistic models and, ultimately, the development of more effective or tolerable biological interventions. Leveraging our team’s unique multidisciplinary expertise and productive track record of NIH-sponsored research, this project will use an innovative combination of paranoia assessments, advanced neuroimaging techniques, and smartphone-based experience sampling to clarify the factors governing paranoia. We will enroll the full spectrum of paranoia without gaps or discontinuities—including psychosis patients with frank persecutory delusions and matched community controls. These data will allow us to rigorously examine the hypothesized contribution of brain circuits responsible for triggering anxiety and evaluating the threat potential of everyday social cues, such as faces. Integrating neuroimaging measures with experience-sampling data will enable us to extend these insights to the real world—a key step to establishing therapeutic relevance—for the first time. It has become increasingly clear that categorical psychiatric diagnoses (e.g. schizophrenia) present significant barriers to understanding pathophysiology. Our focus on dimensional measures of paranoia overcomes many of these barriers and dovetails with the National Institute of Mental Health’s Strategic Objectives and Research Domain Criteria (RDoC) initiative. This work would provide a potentially transformative opportunity to test and refine theory, deepen our understanding of etiology, guide the development of new translational models, discover new treatment targets, and provide an integrative biopsychosocial framework for unifying research across investigators, approaches, and scholarly guilds.