Lancet 2021; 398: Series: Heat and Health Hot weather and heat extremes harm human health, with poverty, ageing, and chronic illnesses as aggravating factors. As the global community contends with even hotter weather in a changing climate, there is a pressing need to better understand the most effective prevention and response measures, particularly in low-resource settings. In this two-paper series, the physiological, social, and environmental factors that contribute to individual heat vulnerability, and the megatrends affecting future heat-related morbidity and mortality at the population level, are comprehensively reviewed. Solutions to address the physiological heat strain that underlies the negative health effects of heat extremes and hot weather, which can be employed across a range of settings at individual, building, and landscape scales, are presented.