The wide circulation of substandard medicines in Southeast Asia is a serious public health concern. Substandard medicines may contain none, or inadequate quantities of the active ingredient, or may contain harmful ingredients. This poses a considerable threat to human lives and an obstacle to infectious disease control at the national, regional and global level, also due to the associated risk of antimicrobial resistance. As trade liberalisation in the region intensifies, moreover, there are concerns that reduced custom controls and higher mobility of people and goods may increase the illicit trade in falsified medicines. In this context, crucial is the ability of governments to develop adequate regulations and capacities as well as enforcement measures to tackle these issues. Given the transnational nature of the problem, the establishment of effective mechanisms for cross-country surveillance, information exchange and coordinated action is also necessary. In this article, we provide an overview of national responses, reflecting on strengths and limitations of past interventions. We then examine existing institutional frameworks for regional health cooperation, particularly the Association of Southeast Asian Nations, and their potential to support enhanced capacities and cooperation to address this challenge.