As efforts to build emergency-ready health systems intensify across the globe, Strategic Investment for Health System Resilience: A Three-Layer Framework provides a practical investment framework and a diverse set of country cases to inform decision-making and strategic resource allocations. The framework includes layer 1, risk reduction―promoting emergency-ready primary health care, public health, prevention, and community preparedness; layer 2, detection, containment, and mitigation capabilities; and layer 3, advanced case management and surge response. This three-layer framework prioritizes interventions that prevent a public health threat from developing in the first place (layer 1), limit its spread should one emerge (layer 2), and manage a widespread crisis that compromises a health system’s ability to deliver care sustainably (layer 3). All three layers play a role in achieving health system resilience, but not all of them have been leveraged equally in the past. Strategic Investment for Health System Resilience offers a glimpse of the relatively low cost of investments in improving the operation of the weakest parts of the three layers. Layer 1 functions are estimated to cost between US$2 per capita in low-income countries and US$4 per capita in lower-middle-income countries. The framework applies equally to short-term epidemics of communicable diseases and to slow-moving trends in noncommunicable diseases. The pace of the needed response to health threats can vary, but all require a system that is resilient across multiple layers of response. Although there is no universal blueprint for every setting, it behooves all countries to seize the moment and invest in the three layers in ways that fit their needs.