This study examines the impact of a changing climate on heat-related mortality in 40 large cities in the United States. A synoptic climatological procedure, the spatial synoptic classification, is used to evaluate present climate-mortality relationships and project how potential climate changes might affect these values. Specifically, the synoptic classification is combined with downscaled future climate projections for the decadal periods of 2020-29, 2045-55, and 2090-99 from a coupled atmospheric-oceanic general circulation model. The results show an increase in excessive heat event (EHE) days and increased heat-attributable mortality across the study cities with the most pronounced increases projected to occur in the Southeast and Northeast. This increase becomes more dramatic toward the end of the twenty-first century as the anticipated impact of climate change intensifies. The health impact associated with different emissions scenarios is also examined. These results suggest that a "business as usual'' approach to greenhouse gas emissions mitigation could result in twice as many heat-related deaths by the end of the century than a lower emissions scenario. Finally, a comparison of future estimates of heat-related mortality during EHEs is presented using algorithms developed during two different, although overlapping, time periods, one that includes some recent large-scale significant EHE intervention strategies (1975-2004), and one without (1975-95). The results suggest these public health responses can significantly decrease heat-related mortality.