The Homestake shear zone, one of the principal Precambrian structures within the Colorado mineral belt, has a history of tectonism that extends from the Proterozoic to the Tertiary. New field mapping, microstructural analysis, and electron-microprobe U-Th-Pb monazite dates define the style, kinematics, and timing of multistage Proterozoic ductile deformation. Early subhorizontal shearing (D1) progressed to northwest-southeast crustal shortening (D2) during a protracted ca. 1710–1630 Ma orogeny involving high-temperature metamorphism, partial melting, and emplacement of the ca. 1.7 Ga Cross Creek batholith. The subvertical, northeast trend of the shear zone was established by D2 shortening. A major episode of simple-shear displacement occurred ca. 1.4 Ga during emplacement of the St. Kevin batholith. Complex kinematics are recorded by 1380 Ma, southeast- side-down, dextral mylonite zones (D3) and post–1380 Ma southeast-side-up, dextral ultramylonite-pseudotachylyte zones (D4) that were both localized in D2 foliation domains. The succession of ductile tectonites in the Homestake records >300 m.y. of episodic deformation at progressively shallower crustal levels as Colorado evolved from an active accretionary margin (1.8–1.7 Ga), through crustal assembly (1.7–1.6 Ga), to a tectonically active continental interior (post 1.45 Ga). The Homestake shear zone constitutes a classic example of ductile shear-zone reactivation and the development of persistent tectonic zones in the continental lithosphere.