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Advances in observational, laboratory, and modeling techniques open the way to the development of physical models of the seismic cycle with potentially predictive power. To explore that possibility, we developed an integrative and fully dynamic model of the Parkfield segment of the San Andreas Fault. The model succeeds in reproducing a realistic earthquake sequence of irregular moment magnitude (Mw) 6.0 main shocks—including events similar to the ones in 1966 and 2004—and provides an excellent match for the detailed interseismic, coseismic, and postseismic observations collected along this fault during the most recent earthquake cycle. Such calibrated physical models provide new ways to assess seismic hazards and forecast seismicity response to perturbations of natural or anthropogenic origins.