Earthquake instability requires fault weakening during slip. The mechanism of this weakening is central to understanding earthquake sliding and, in many cases, has been attributed to fluids. It is also unclear why major faults such as the San Andreas Fault do not exhibit significant thermal anomalies due to shear heating during sliding and whether or not fault rocks that have been melted—pseudotachylytes—are rare. High-speed friction experiments on a wide variety of rock types have shown that they all exhibit extreme weakening and that the sliding surface is nanometric and contains phases not present at the start. Here we use electron microscopy to examine these two key observations in high-speed friction experiments and compare them with high-pressure faulting experiments. We show that phase transformations occur in both cases and that they are associated with profound weakening. However, fluid is not necessary for such weakening; the nanometric fault filling is inherently weak at seismic sliding rates and it flows by grain boundary sliding. These observations suggest that pseudotachylytes are rare in nature because shear-heating-induced endothermic reactions in fault zones prevent temperature rise to melting. Microstructures preserved in the Punchbowl Fault, an ancestral branch of the San Andreas Fault, suggest similar processes during natural faulting and offer an explanation for the lack of a thermal aureole around major faults.