COVID-19 was not a black swan event. The emergence and spread of COVID-19 have dramatically highlighted the vital interest for the US and the global community to counter and manage the persistent risk of the biosecurity threats posed by infectious diseases, whether arising naturally, through accidents with high-consequence pathogens, or via deliberate release of harmful bioagents (Miley in Global health security: recognizing vulnerabilities, creating opportunities. Springer Publishing, 2020). For years stemming from our experience with SARS, H1N1 and Ebola, Public Health and foresight experts have been calling attention to the global and national security impacts of global outbreaks. COVID-19 has in fact stress tested our national and global security revealing inherent vulnerabilities within our societal systems and infrastructure in addition to vulnerabilities and shortcomings associated with our mitigation, preparedness and response capabilities. Given the impacts of COVID-19 on national and global security and the risks pertaining to the increasing frequency and severity of upcoming pathogens, there is an urgent demand for novel approaches and capabilities to detecting and responding to pandemic threats. As described in Tõnurist and Hanson (Anticipatory innovation governance: Shaping the future through proactive policy making. OECD working papers on public governance, no 44. OECD Publishing, Paris, 2020.  https://doi.org/10.1787/cce14d80-en .) ‘…even though foresight tools are increasingly integrated into policymaking, governments often lack a practical understanding of how to anticipate uncertain futures but also how to act on them today to achieve desired outcomes’. Our premise is that assessing and tackling the future risks stemming from pandemic threats requires innovative, collaborative approaches that draw on diverse capacities in the areas of AI-driven disease sensing, large-scale data-driven epidemic modelling, multi-scaled projections of socio-ecological risks, big data, systems and futures thinking, policy analysis, human resource development, and knowledge exchange. This chapter presents a complexity-informed inquiry challenging traditional mindsets and practices to support anticipatory innovation that enables next generation pandemic preparedness and response capability-based planning.