Abstract Abundant heterogeneity has been documented on faults in nature across a wide range of length scales, including structural, mineralogical, and roughness variations. The role of complex heterogeneity on fault mechanics and frictional stability is not well established, and experiments investigating heterogeneity have typically incorporated a single source of heterogeneity. Here, we conduct rock friction experiments on rough, bimaterial faults that are creeping, or steadily sliding, to explore the role of lithological heterogeneity on fault mechanics and stability. When strong asperities juxtapose weak gouge, stable sliding occurs with a low friction coefficient, µ. Encounters of strong diabase asperities on talc gouge lined faults initiate dramatic increases in µ and transitions to unstable sliding characterized by frequent stick-slip events (StSE). Seismic moments and stress drops of StSE decrease with increasing asperity abundance. Stress is concentrated at asperities during encounters, increasing with decreasing asperity abundance and leading to extensive mechanical damage. Interactions between strong, velocity weakening asperities provide a model to explain the nucleation of seismic and aseismic slip events on nominally stable, creeping faults.