This paper highlights and expands on the extensive work concerning extreme heat events, and the environmental and societal factors that affect human health. Selections of this work were presented originally in a Union of Concerned Scientists public report (‘Heat in the Heartland’). As humans respond concomitantly to a suite of meteorological variables, we accordingly aim to examine summertime frequencies and characteristics of select synoptic weather types in the Midwestern United States, particularly those associated with elevated health impacts risk. We analyse five major urban centres, paired with five nearby smaller cities, to investigate the potential relative differences due to urban form and size. In virtually all of these locales, the frequency of health-debilitating hot weather types has increased in the six most recent decades, with many of these also demonstrating statistically significant upward trends in air and dew point temperatures. This is most prevalent for overnight temperatures, where the hottest weather types display increasing overnight temperatures in both large and small cities, thus causing the diurnal temperature ranges to decrease. Furthermore, the prevalence of three or more consecutive runs of these days is on the rise, with all five large cities experiencing a higher number of heat waves today than in the late 1940s. We emphasize the importance of city-level efforts to assist in minimizing future climate-related health risks. Finally, we demonstrate the increasing human mortality response in one select city (Detroit, MI), which is estimated without the presence of city-level efforts, targeted interventions, adaptation strategies, or physiological acclimatization. This highlights the importance of providing accurate heat-health warnings to the public, and provides essential understanding of the Midwest US region's summertime climate trends.