Extreme heat poses an immediate and significant threat to public health that is projected to increase in frequency and severity in coming years. Individuals who are unable to limit heat exposure due either to a lack of resources (e.g., persons without home air conditioning) or their occupation (e.g., construction workers, military personnel) and persons with decrements in physiological function (e.g., older adults with chronic conditions) are among the most vulnerable. To mitigate heat-related morbidity and mortality in these individuals, there is an urgent need to develop both effective and feasible cooling strategies across a broad range of environmental and work conditions. This Primer is directed at supporting interdisciplinary efforts in this area by describing the physiological and biophysical processes of body temperature regulation during heat stress, the role of these processes in the development of acute injury, and how they dictate the effectiveness of cooling strategies. We hope that with this information, readers will be better equipped to design and shape heat-resilient cities and communities.