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Several neurochemical systems converge in the prefrontal cortex (PFC) to regulate cognitive and motivated behaviors. A rich network of endogenous opioid peptides and receptors spans multiple PFC cell types and circuits, and this extensive opioid system has emerged as a key substrate underlying reward, motivation, affective behaviors, and adaptations to stress. Here, we review the current evidence for dysregulated cortical opioid signaling in the pathogenesis of psychiatric disorders. We begin by providing an introduction to the basic anatomy and function of the cortical opioid system, followed by a discussion of endogenous and exogenous opioid modulation of PFC function at the behavioral, cellular, and synaptic level. Finally, we highlight the therapeutic potential of endogenous opioid targets in the treatment of psychiatric disorders, synthesizing clinical reports of altered opioid peptide and receptor expression and activity in human patients and summarizing new developments in opioid-based medications. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models"., Competing Interests: Declaration of Competing Interest This work was supported by the National Institutes of Health [grant numbers R00AA027806 amd R00DA048085], the Whitehall Foundation [grant number 2022-08-005], and the Brain and Behavior Research Foundation. RHC was supported by the Center for Neuroscience at the University of Pittsburgh. The authors declare no potential conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)