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Description: The apparent stochastic nature of earthquakes poses major challenges for earthquake forecasting attempts. Physical constraints on the seismogenic potential of major fault zones may aid in improving seismic hazard assessments, but the mechanics of earthquake nucleation and rupture are obscured by the complexity that faults display. In this work, we investigate the mechanisms behind giant earthquakes by employing a microphysically based seismic cycle simulator. This microphysical approach is directly based on the mechanics of friction as inferred from laboratory tests, and can explain a broad spectrum of fault slip behaviour. We show that regular earthquakes are controlled by the size and distribution of nominally unstable asperities, whereas fault-spanning earthquakes are governed by a rheological transition occurring in creeping fault segments. Moreover, this facilitates the nucleation of giant earthquakes on faults that are weakly seismically coupled. This microphysically based approach offers opportunities for investigating long-term seismic cycle behaviour of natural faults.