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Despite comprising one-fifth of the population, individuals living in rural areas are underrepresented in clinical trials on substance use disorders (SUD). The inclusion of rural residents is critical to reducing disparities in health outcomes and improving adoption of evidence-based interventions for SUDs. The current commentary provides five guiding principles to assist researchers in including rural populations in trials. These principles emphasize including rural communities in the study design phase and throughout the research process, understanding the local rural context, consideration of operationalization of rural in research, suggested adaptions for research, and embracing opportunities for bi-directional and sustainable partnerships. When approached thoughtfully, research funding can catalyze rural capacity, foster durable partnerships, and enrich scientific inference to assist in establishing the evidence-base for SUD research.