The Department of Health and Human Services, through the National Institutes of Health (NIH), invites applications for the "Exploratory Clinical Neuroscience Research on Substance Use Disorders" funding opportunity (NOFO PAR-23-157). This program supports exploratory clinical research aimed at understanding the neurobiological mechanisms of substance use disorders (SUD) over a five-year period under the phased R61/R33 award structure. Eligible applicants can include various educational and governmental institutions, nonprofits, and for-profit organizations. The program seeks innovative projects that address the neurobiology of SUD and their risk factors, including neural circuitry and behavioral processes. Funding can amount to $500,000 for the R61 phase and an unrestricted budget in the R33 phase, contingent upon meeting specific R61 milestones. Applications must propose measurable milestones and demonstrate a pathway from R61 to R33. Key dates include an application deadline of June 21, 2023, with subsequent review cycles. Eligible applicants are encouraged to contact program staff prior to submission, and adherence to guidelines and instructions in the SF424 application guide is essential. This initiative seeks to advance research in response to the ongoing public health challenge surrounding substance use, especially in light of the opioid crisis and emerging substance trends.