Sudden cardiac arrest (SCA) is one of the largest causes of mortality globally, with an out-of-hospital survival below 10% despite intense research. This document outlines challenges in addressing the epidemic of SCA, along the framework of respond, understand and predict, and prevent. Response could be improved by technology-assisted orchestration of community responder systems, access to automated external defibrillators, and innovations to match resuscitation resources to victims in place and time. Efforts to understand and predict SCA may be enhanced by refining taxonomy along phenotypical and pathophysiological “axes of risk,” extending beyond cardiovascular pathology to identify less heterogeneous cohorts, facilitated by open-data platforms and analytics including machine learning to integrate discoveries across disciplines. Prevention of SCA must integrate these concepts, recognizing that all members of society are stakeholders. Ultimately, solutions to the public health challenge of SCA will require greater awareness, societal debate and focused public policy.