Global climate change is projected to increase the frequency and duration of periods of extremely high temperatures. Both the general populace and public health authorities often underestimate the impact of high temperatures on human health. To highlight the vulnerable populations and illustrate approaches to minimization of health impacts of extreme heat, the authors reviewed the studies of heat-related morbidity and mortality for high-risk populations in the U.S. and Europe from 1958 to 2012. Heat exposure not only can cause heat exhaustion and heat stroke but also can exacerbate a wide range of medical conditions. Vulnerable populations, such as older adults; children; outdoor laborers; some racial and ethnic subgroups (particularly those with low SES); people with chronic diseases; and those who are socially or geographically isolated, have increased morbidity and mortality during extreme heat. In addition to ambient temperature, heat-related health hazards are exacerbated by air pollution, high humidity, and lack of air-conditioning. Consequently, a comprehensive approach to minimize the health effects of extreme heat is required and must address educating the public of the risks and optimizing heatwave response plans, which include improving access to environmentally controlled public havens, adaptation of social services to address the challenges required during extreme heat, and consistent monitoring of morbidity and mortality during periods of extreme temperatures.