Migraine is a leading cause of disability worldwide. Despite the recent approval of several calcitonin gene-related peptide-targeted therapies, many people with migraine do not achieve satisfactory headache improvement with currently available therapies and there continues to be an unmet need for effective and tolerable migraine-specific treatments. Exploring additional targets that have compelling evidence for their involvement in modulating migraine pathways is therefore imperative. Potential new therapies for migraine include pathways involved in nociception, regulation of homoeostasis, modulation of vasodilation, and reward circuits. Animal and human studies show that these targets are expressed in regions of the CNS and peripheral nervous system that are involved in pain processing, indicating that these targets might be regarded as promising for the discovery of new migraine therapies. Future studies will require assessment of whether targets are suitable for therapeutic modulation, including assessment of specificity, affinity, solubility, stability, efficacy, and safety., Competing Interests: Declaration of interests C-CC has served on the advisory board for Satsuma and eNeura and receives research support from the American Heart Association with funds paid to her institution. FP receives research support from AbbVie, Lundbeck, PeptideLogic, and AstraZeneca, with funds paid to his institution. He is a cofounder of Catalina Pharma and Axon Therapeutics. CER has previously served on advisory boards for Lundbeck, Biohaven, Impel, Linpharma, and Satsuma. She receives research support from Teva, Pfizer, and Lundbeck, with funds paid to her institution. She also receives royalties as author and associate editor for UpToDate. DWD has received consulting fees from Amgen, Atria, CapiThera, Cerecin, Ceruvia Lifesciences, CoolTech, Ctrl M, Allergan, AbbVie, Biohaven, GlaxoSmithKline, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Genentech, Nocira, Perfood, Praxis, AYYA Biosciences, Revance, and Pfizer; honoraria from the American Academy of Neurology, Headache Cooperative of the Pacific, Canadian Headache Society, Medic Footprints Medical Education Research, Biopharm Communications, Clinical Education Alliance Group Holding Company, Vector Psychometric Group, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin, Medlogix Communications, Medica Communications, MJH Life Sciences, Miller Medical Communications, WebMD Health, Medscape, Wolters Kluwer, Oxford University Press, and Cambridge University Press; and speaking fees from Teva, Amgen, Eli Lilly, Lundbeck, and Pfizer; serves as a non-profit board member for the American Brain Foundation, American Migraine Foundation, ONE Neurology, Precon Health Foundation, International Headache Society Global Patient Advocacy Coalition, Atria Health Collaborative, Arizona Brain Injury Alliance, and Domestic Violence HOPE Foundation and Panfila; has received research support from the US Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, and Patient Centered Outcomes Research Institute; has stock options or patents, is a shareholder of, or serves on the board of directors of Aural Analytics (options), Axon Therapeutics, ExSano (options), Palion (options), Man and Science, Healint (options), Theranica (options), Second Opinion and Mobile Health (options), Epien (options and board member), Nocira (options), Matterhorn (shares and board member), Ontologics (shares and board member), King-Devick Technologies (options and board member), Precon Health (options and board member), AYYA Biosciences (options), Axon Therapeutics (options and board member), Cephalgia Group (options and board member), Atria Health (options and employee); and has a non-royalty bearing patent 17189376.1-1466:v (Onabotulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis; and has a patent application submitted for Synaquell (Precon Health)., (Copyright © 2024 Elsevier Ltd. All rights reserved.)