Many active faults are expected to develop fluid pressures in excess of hydrostatic pressures below 3 to 7 km depth during interseismic periods. Suprahydrostatic fluid pressures are known to reduce the stresses required for brittle failure. Stress differences that trigger moderate to large earthquakes typically range from 40 to 160 MPa, as indicated by earthquake shear stress drops and paleostress estimates obtained from mylonites. For stresses in this range (40–160 MPa), seismic fault reactivation requires in most cases pore fluid factors (fluid pressure/overburden pressure) higher than for hydrostatic fluid pressures (i.e., >0.37) along misoriented faults with fault angles ≥45°, such as many segments of the San Andreas fault system. For example, at a stress difference of 100 MPa and fault angles of 45°–55°, fault reactivation at 7 to 20 km depth requires hypocentral pore fluid factors of ≈0.8–1 for reverse faults, 0.6–0.9 for strike‐slip faults, and <0.8 for normal faults. Pore fluid factors increase with increasing cohesive strength of faults, increasing coefficient of internal friction, and increasing fault angle. Seismic reactivation of cohesive faults at stress differences of 40–160 MPa requires near the base of the seismogenic zone (≈15 km depth) suprahydrostatic fluid pressures at all possible fault angles. Pore fluid factors are ≈0.4–0.9 for normal faults, ≈0.6–1 for strike‐slip faults, and ≈0.8–1.05 for thrust or reverse faults. These constraints are potentially useful for the modelling of seismic faulting and earthquake recurrence times.