This article discusses how decision-makers can be supported to strengthen a culture of prevention. This article presents an example of the United Nations Office on Drugs and Crime’s (UNODC) work to engage with decision-makers to create readiness, demand, and capacity for evidence-based prevention programming among them, particularly in low- and middle-income countries. First, we utilized two of the UNODC’s data sources to describe the context where the UNODC’s prevention efforts take place. Analysis of the first dataset on prevention activities implemented globally revealed a gap in translating evidence into practice on a global scale. The second dataset consisted of UNODC policy documents mandating and guiding global action to address substance use. The analysis showed that at the level of political frameworks, prevention is gradually gaining more attention but is still frequently left in the shadow of health- and law enforcement-related issues. In addition, these guiding documents did not reflect fully the current scientific understanding of what constitutes an effective prevention response. Against this background, the feasibility of the UNODC’s efforts to bridge the science–practice gap in the field of prevention was discussed by presenting the results from the UNODC’s regional capacity-building seminars focused on the role of monitoring and evaluation in prevention programming. The results showed potential of this capacity building to affect the attitudes and knowledge of targeted decision-makers. Such efforts to increase decision-makers’ readiness and ultimately their endorsement, adoption, and ongoing support of evidence-based preventive interventions should be continued and intensified.