Cannabis-related issues for adolescents and young adults are emerging from the shadow of rural opioid addiction and deaths. The rural pediatric population has multiple risk factors putting them at increased risk for adverse consequences with the expansion of cannabis legalization across the United States. Research in this area is rich but scattered across professional disciplines. Differences in demographics and cultures between rural and urban youth are gaining attention. Epidemiological factors relevant to rurality as a risk for cannabis and other substance use are considered for formulating clinical care, public policymakers, and future research. Race, culture, community stability, basic demographics of age, gender, educational status, and demands for more and better, accessible services for rural, nonmetropolitan areas comprise factors for consideration and are detailed. Research findings provide direction for policymakers and clinicians for prevention and intervention efforts to improve care for rural populations, validating and expanding upon insights gained to date.