The Department of Health and Human Services, through the National Institutes of Health (NIH), issued a Notice of Funding Opportunity (NOFO) to support exploratory clinical neuroscience research on substance use disorders (SUD) via an R61/R33 phased grant mechanism. The initiative aims to enhance understanding of the neurobiological mechanisms underlying SUD, enabling innovative studies that explore fundamental circuitry and behaviors pertinent to substance use. The program prioritizes clinical research that falls within the definitions of both basic research and clinical trials, pushing for experimental studies with a focus on the underlying mechanisms of SUD. Key components include a phased funding approach, with the potential for up to five years of support—two for the R61 phase and three for the R33 phase, based on the successful achievement of defined milestones. The NOFO encourages applicants from diverse institutions, including higher education and non-profit organizations, to propose novel studies that probe individual differences in neural circuitry, cognitive processes, and interactions with other psychiatric disorders. Applications must adhere to specific guidelines regarding milestones, data management, and submission processes. The overarching aim is to drive scientific breakthroughs in understanding and combating substance use disorders, aligning with current public health priorities amidst rising drug use challenges.