In today's global society, infectious disease outbreaks can spread quickly across the world, fueled by the rapidity with which we travel across borders and continents. Historical accounts of influenza pandemics and contemporary reports on infectious diseases clearly demonstrate that poverty, inequality, and social determinants of health create conditions for the transmission of infectious diseases, and existing health disparities or inequalities can further contribute to unequal burdens of morbidity and mortality. Yet, to date, studies of influenza pandemic plans across multiple countries find little to no recognition of health inequalities or attempts to engage disadvantaged populations to explicitly address the differential impact of a pandemic on them. To meet the goals and objectives of the Global Health Security Agenda, we argue that international partners, from WHO to individual countries, must grapple with the social determinants of health and existing health inequalities and extend their vision to include these factors so that disease that may start among socially disadvantaged subpopulations does not go unnoticed and spread across borders. These efforts will require rethinking surveillance systems to include sociodemographic data; training local teams of researchers and community health workers who are able to not only analyze data to recognize risk factors for disease, but also use simulation methods to assess the impact of alternative policies on reducing disease; integrating social science disciplines to understand local context; and proactively anticipating shortfalls in availability of adequate healthcare resources, including vaccines. Without explicit attention to existing health inequalities and underlying social determinants of health, the Global Health Security Agenda is unlikely to succeed in its goals and objectives.