Nonmedical prescription opioid misuse remains a growing public problem in need of action and is concentrated in areas of US states with large rural populations such as Kentucky, West Virginia, Alaska, and Oklahoma. We developed hypotheses regarding the influence of 4 factors: (1) greater opioid prescription in rural areas, creating availability from which illegal markets can arise; (2) an out-migration of young adults; (3) greater rural social and kinship network connections, which may facilitate drug diversion and distribution; and (4) economic stressors that may create vulnerability to drug use more generally. A systematic consideration of the contexts that create differences in availability, access, and preferences is critical to understanding how drug use context varies across geography.