Thermal extremes are responsible for more than 90% of all weather-related deaths in the United States, with heat alone accounting for an annual death toll of 618. With the combination of global warming and urban expansion, cities are becoming hotter and the threat to the well-being of citizens in urban areas is growing. Because people in modern societies (and in particular, vulnerable groups such as the elderly) spend most of their time inside their home, indoor exposure to heat is the underlying cause in a considerable fraction of heat-related morbidity and mortality. Notably, this can be observed in many US cities despite the high prevalence of mechanical air conditioning in the building stock. Therefore, part of the effort to reducing the overall vulnerability of urban populations to heat needs to be dedicated to understanding indoor exposure, its underlying behavioral and physical mechanisms, health outcomes, and possible mitigation strategies. This dissertation is an effort to advance the knowledge in these areas. The cities of Houston, TX, Phoenix, AZ, and Los Angeles, CA, are used as test beds to assess exposure and vulnerability to indoor heat among people 65 and older. Measurements and validated whole-building simulations were used in conjunction with heat-vulnerability surveys and epidemiological modelling (of collaborators) to (1) understand how building characteristics and practices govern indoor exposure to heat among the elderly; (2) evaluate mechanical air conditioning as a reliable protective factor against indoor exposure to heat; and (3) identify potential impacts from the evolving building stock and a warming urban climate. The results show strong associations between indoor heat exposure and certain health outcomes and highlight the vulnerability of elderly populations to heat despite the prevalence of air conditioning systems. Given the current construction practices and urban warming trends, this vulnerability will continue to grow. Therefore, policies promoting climate adaptive buildings features, as well as better access to reliable and affordable AC are needed. In addition, this research draws attention to the significant potential health consequences of large-scale power outages and proposes the implementation of passive survivability in regulations as one important preventative action.