The Salado River fault (SRF) is a prominent structure in southern Mexico that shows evidence of reactivation at two times under different tectonic conditions. It coincides with the geological contact between a structural high characterized by Palaeozoic basement rocks to the north, and an ∼2000 m thick sequence of marine and continental rocks that accumulated in a Middle Jurassic–Cretaceous basin to the south. Rocks along the fault within a zone up to 150 m across record crystal-plastic deformation affecting the metamorphic basement of the Palaeozoic Acatlán Complex. Later brittle deformation is recorded by both the basement and the overlying Mesozoic sedimentary rocks. Regional features and structural textures at both outcrop and microscopic scale indicate two episodes of left-lateral displacement. The first took place under low-to medium-grade P-T conditions in the late Early Jurassic (180 Ma) based on the interpretation of 40Ar/39Ar ratios from muscovite within the fault zone; the second occurred under shallow conditions, when the fault served as a transfer zone between areas with differing magnitudes of shortening north and south of the fault. In the southern block, fold hinges were dragged westward during Laramide tectonic transport to the east, culminating in brittle deformation characterized by strike–slip faulting in the Mesozoic sedimentary rocks. North of the fault, folds are not well defined, and it is clear that the fold hinges observed in the southern block do not continue north of the fault. Although the orientation and kinematics of the SRF are similar to major Cainozoic shear zones in southern Mexico, our new data indicate that the fault had become inactive by the time of Oligocene volcanism.