The prohibition approach to narcotics control has been in existence for decades with little or no change to the existing policy. This article explores the global drug prohibition regime, the quest for policy change and why the US matters to any change in policy. Drawing on key scholarly works and interviews from experts in the field, the article employs the theory of policy paradigm (orders of change) to explain the types of policy change occurring within the US/global narcotics regime. The hegemonic stability theory also provides some explanations for the dominant role of the US in shaping the global narcotics regime. The key finding reveals that the US and the global narcotics regime are undergoing first and second order changes in policy.