Earthquake ruptures that nucleate along faults at depth can only propagate to the Earth's surface if the shear stresses during faulting exceed the yield strength of the uppermost crust, where fluid pressures are usually hydrostatic. Suprahydrostatic fluid pressures may be required at depth for the seismic reactivation of misoriented faults, such as the San Andreas fault system. Based on fracture criteria for the wall and fault rock, slip events that can cause ground breakage are estimated to occur at seismogenic depth along fault planes that form angles of less than 65¿ on average with the maximum principal stress direction. Such slip events require minimum shear stresses of about 30 MPa at hypocentral depth. For faults with long interseismic periods, and thus, inferred high cohesive strength, the predicted reactivation angle is ≤55¿, suggesting that several segments of the San Andreas fault system in southern California, including the San Bernardino area, parts of the Elsinore fault zone and the San Jacinto fault, provide the most probable hypocentral sites for future large earthquakes that disrupt the surface. To provide further constraints on locations for such earthquakes, we urgently need to investigate frictional properties of fault rocks and the state of stress at depth by employing laboratory experiments, focal mechanism studies, and by drilling into seismically active faults such as the San Andreas fault system. ¿ 1999 American Geophysical Union