Increasing severity of extreme heat is a hallmark of climate change. Its impacts depend on temperature but also on moisture and solar radiation, each with distinct spatial patterns and vertical profiles. Here, we consider these variables’ combined effect on extreme heat stress, as measured by the environmental stress index, using a suite of high-resolution climate simulations for historical (1980–2005) and future (2074–2099, Representative Concentration Pathway 8.5 (RCP8.5)) periods. We find that observed extreme heat stress drops off nearly linearly with elevation above a coastal zone, at a rate that is larger in more humid regions. Future projections indicate dramatic relative increases whereby the historical top 1% summer heat stress value may occur on about 25%–50% of future summer days under the RCP8.5 scenario. Heat stress increases tend to be larger at higher latitudes and in areas of greater temperature increase, although in the southern and eastern US moisture increases are nearly as important. Imprinted on top of this dominant pattern we find secondary effects of smaller heat stress increases near ocean coastlines, notably along the Pacific coast, and larger increases in mountains, notably the Sierra Nevada and southern Appalachians. This differential warming is attributable to the greater warming of land relative to ocean, and to larger temperature increases at higher elevations outweighing larger water-vapor increases at lower elevations. All together, our results aid in furthering knowledge about drivers and characteristics that shape future extreme heat stress at scales difficult to capture in global assessments.