[1] The devastation inflicted by recent earthquakes demonstrates the danger of under-predicting the size of earthquakes. Unfortunately, earthquakes may rupture fault-sections larger than previously observed, making it essential to develop predictive rupture models. We present numerical models based on earthquake physics and fault zone data, that determine whether a rupture on a segmented fault could cascade and grow into a devastating, multisegment earthquake. We demonstrate that weakened (damaged) fault zones and bi-material interfaces promote rupture propagation and greatly increase the risk of cascading ruptures and triggered seismicity. This result provides a feasible explanation for the outstanding observation of a very large (10 km) rupture jump documented in the M W 7.8 2001 Kunlun, China earthquake. However, enhanced inter-seismic deformation and energy dissipation at fault tips suppress rupture propagation and may turn even small discontinuities into effective earthquake barriers. By assessing fault stability, identifying rupture barriers and foreseeing multisegment earthquakes, we provide a tool to improve earthquake prediction and hazard analysis.