Stress transfer from the great 1964 Prince William Sound earthquake is modeled on the Denali fault, including the Denali–Totschunda fault segments that ruptured in 2002, and on other regional fault systems where M 7.5 and larger earthquakes have occurred since 1900. The results indicate that analysis of Coulomb stress transfer from the dominant earthquake in a region is a potentially powerful tool in assessing time-varying earthquake hazard. Modeled Coulomb stress increases on the northern Denali and Totschunda faults from the great 1964 earthquake coincide with zones that ruptured in the 2002 Denali fault earthquake, although stress on the Susitna Glacier thrust plane, where the 2002 event initiated, was decreased. A southeasterly-trending Coulomb stress transect along the right-lateral Totschunda–Fairweather–Queen Charlotte trend shows stress transfer from the 1964 event advancing slip on the Totschunda, Fairweather, and Queen Charlotte segments, including the southern Fairweather segment that ruptured in 1972. Stress transfer retarding right-lateral strike slip was observed from the southern part of the Totschunda fault to the northern end of the Fairweather fault (1958 rupture). This region encompasses a gap with shallow thrust faulting but with little evidence of strike-slip faulting connecting the segments to the northwest and southeast. Stress transfer toward failure was computed on the north–south trending right-lateral strike-slip faults in the Gulf of Alaska that ruptured in 1987 and 1988, with inhibitory stress changes at the northern end of the northernmost (1987) rupture. The northern Denali and Totschunda faults, including the zones that ruptured in the 2002 earthquakes, follow very closely (within 3%), for about 90°, an arc of a circle of radius 375 km. The center of this circle is within a few kilometers of the intersection at depth of the Patton Bay fault with the Alaskan megathrust. This inferred asperity edge may be the pole of counterclockwise rotation of the block south of the Denali fault. These observations suggest that the asperity and its recurrent rupture in great earthquakes as in 1964 may have influenced the tectonics of the region during the later stages of evolution of the Denali strike-slip fault system.