Our evolving understanding of the physiologic processes that lead to sepsis has led to updated consensus guidelines outlining priorities in the recognition and treatment of septic patients. However, an enormous question remains when considering how to best implement these guidelines in settings with limited resources, which include rural US emergency departments and low- and middle-income countries. The core principles of sepsis management should be a priority in community emergency departments. Similarly, cost-effective interventions are key priorities in low- and middle-income countries; however, consideration must be given to the unique challenges associated with such settings.