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Overexpressed or dysregulated iNOS has been implicated in numerous pathologies including sepsis, cancer, neurodegeneration, and various types of pain. Extensive knowledge has been accumulated about the roles iNOS plays in different tissues and organs. Additionally, X\u2010ray crystal and cryogenic\u00a0electron microscopy structures have shed new insights on the structure and regulation of this enzyme. Many potent iNOS inhibitors with high selectivity over related NOS isoforms, neuronal NOS, and endothelial NOS, have been discovered, and these drugs have shown promise in animal models of endotoxemia, inflammatory and neuropathic pain, arthritis, and other disorders. A major issue in iNOS inhibitor development is that promising results in animal studies have not translated to humans; there are no iNOS inhibitors approved for human use. In addition to assay limitations, both the dual modalities of iNOS and NO in disease states (ie, protective vs harmful effects) and the different roles and localizations of NOS isoforms create challenges for therapeutic intervention. This review summarizes the structure, function, and regulation of iNOS, with focus on the development of iNOS inhibitors (historical and recent). A better understanding of iNOS\u2019 complex functions is necessary before specific drug candidates can be identified for classical indications such as sepsis, heart failure, and pain; however, newer promising indications for iNOS inhibition, such as depression, neurodegenerative disorders, and epilepsy, have been discovered.\n                  <\/jats:p>","DOI":"10.1002\/med.21599","type":"journal-article","created":{"date-parts":[[2019,6,13]],"date-time":"2019-06-13T07:15:13Z","timestamp":1560410113000},"page":"158-189","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":830,"title":["Inducible nitric oxide synthase: Regulation, structure, and inhibition"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5887-7038","authenticated-orcid":false,"given":"Maris A.","family":"Cinelli","sequence":"first","affiliation":[{"name":"Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics Northwestern University Evanston Illinois"},{"name":"Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics Northwestern University Evanston Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha T.","family":"Do","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics Northwestern University Evanston Illinois"},{"name":"Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics Northwestern University Evanston Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galen 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