We recently advocated for a paradigm shift in alcohol prevention research grounded in complex systems and dynamic modeling methodologies [1,2]. In response, Purshouse and colleagues [3] acknowledged that complex simulation modeling holds promise, and echoed our call for its application while emphasizing the importance of methodological care to ensure that such initiatives are useful. We agree that advanced computational capabilities, as well as policymakers' increased use of evidence, make this the right time to invest in complex simulation modeling. That said, our manuscripts were intended to introduce a programmatic discourse in alcohol prevention that surpasses complex simulation modeling. We hope etiological research, evidence-based policymaking and action planning will embrace a complex-systems-grounded paradigmatic overhaul in alcohol prevention in the context of population health [4,5].Empirical observations suggest that the prevailing paradigm in alcohol prevention offers an incomplete representation of how alcohol misuse develops over time and leads ultimately to inconsequential population-level interventions [1,2,6]. Thus, traditional research and prevention approaches are not designed to capture the complex nature of alcohol misuse. As a complex system, alcohol misuse is: determined by interconnected, heterogeneous, self-organizing and evolving subsystems [1,2]; marked by dynamic complexity, non-linear feedbacks, phase transitions and emergence across temporal scales [1,2]; defined by the presence of mutual and adversely reinforcing risks [6]; and exacerbated by risk disparities associated with social, economic and geographic milieux in which populations at-risk are immersed [6]. As with other complex systems [7,8], alcohol misuse is particularly difficult to control because it often switches from manageable to uncontrollable or irreversible states [6]. While complex simulation modeling can provide useful insights, it unfortunately falls short of capturing the wide array of dynamic properties that determine systemic failures in alcohol misuse. The untapped potential of integrative, transdisciplinary complexsystems-grounded epistemological, methodological and analytical frameworks offers a path to illuminating the mechanisms that determine stability, resilience and predictability in protracted population health challenges and support more impactful action [5].The foundational blocks of the comprehensive complexsystems-grounded paradigmatic shift in alcohol prevention we are advocating include: (a) architectural mapping of the system (e.g. component configuration and interactions) [6]; (b) delineation of the controllability and control principles of the system (e.g. dynamic laws governing the temporal behavior of system components) [6]; (c) development of an integrative theory base grounded in substance prevention (e.g. social networks [7]), population health (e.g. syndemics [8]) and complex systems (e.g. phase transitions) theoretical frameworks; and (d) synergistic methodological and analytical framew...