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More than half of the world's population is living in urban areas, but the evidence about urban–rural differences in drug use is not clearly defined. The present paper aims to review the international literature addressing the role of urbanization and related parameters in association with substance misuse. In particular, the evidence of urbanization being a risk factor for substance misuse is examined.Although it has been suggested that substance misuse is typically a characteristic of large urban areas, this did not appear to be a consistent observation from the literature review. Furthermore, the urban context may offer a relative proximity of health services and prompter emergency intervention in case of overdose.Although more efforts have to be put into explaining substance misuse in general, identifying which characteristics of the urban context are modifiable, and under what circumstances, is an important theoretical, empirical, and public health question.