The Archean Murchison greenstone belt, Limpopo Province, South Africa, represents a rifted epicontinental arc sequence containing the largest volcanic-hosted massive sulfide (VMS) district in Southern Africa. The so-called Cu–Zn line is host to 12 deposits of massive sulfide mineralization including: Maranda J, LCZ, Romotshidi, Mon Desir, Solomons, and Mashawa with a total tonnage of three million metric tons of very high grade Zn, subordinate Cu, and variable Pb and Au ore. The deposits developed during initial phases of highly evolved felsic volcanism between 2,974.8 ± 3.6 and 2,963.2 ± 6.4 Ma and are closely associated with quartz porphyritic rhyolite domes. Elevated heat supply ensured regional hydrothermal convection along the entire rift. Recurrent volcanism resulted in frequent disruption of hydrothermal discharge and relative short-lived episodes of hydrothermal activity, probably responsible for the small size of the deposits. Stable thermal conditions led to the development of mature hydrothermal vent fields from focused fluid discharge and sulfide precipitation within thin layers of felsic volcaniclastic rocks. Two main ore suites occur in the massive sulfide deposits of the “Cu–Zn line”: (1) a low-temperature venting, polymetallic assemblage of Zn, Pb, Sb, As, Cd, Te, Bi, Sn, ±In, ±Au, ±Mo occurring in the pyrite- and sphalerite-dominated ore types and (2) a higher temperature suite of Cu, Ag, Au, Se, In, Co, Ni is associated with chalcopyrite-bearing ores. Sphalerite ore, mineralogy, and geochemical composition attest to hydrothermal activity at relatively low temperatures of ≤250 °C for the entire rift, with short-lived pulses of higher temperature upflow, reflected by proportions of Zn-rich versus Cu-rich deposits. Major- and trace-metal composition of the deposits and Pb isotope signatures reflect the highly evolved felsic source rock composition. Geological setting, host rock composition, and metallogenesis share many similarities not only with Archean VMS districts in Canada and Australia but also with recent arc–back-arc systems on the modern seafloor where fragments of continental crust and areas of elevated heat flow are involved in petrogenetic and associated metallogenic processes.