The Tethyan domain hosts the world's most abundant Mississippi Valley-Type (MVT) Pb-Zn deposits, which occur in fold-thrust belts and forelands on both sides of the continent-continent collisional zone through the whole Tethyan domain. Mineralization commonly took place when the ore districts were experiencing strike-slip or extensional deformation, which occurred after regional compression or during the late stage of a compressional deformation event. The main ore-controlling factors include extensional faults, evaporite diapir, carbonate dissolution and collapse, evaporite dissolution and collapse, porous dolostone, and barite-bearing strata. Records of hydrocarbon fluids are present in many Pb-Zn deposits and ore districts of the Tethyan domain. They reacted with (dissolved) sulfate to provide reduced sulfur for the ore formation. The generation of such abundant MVT Pb-Zn deposits in the Tethyan domain can be attributed to the continent-continent collisional tectonic setting, large amounts of evaporites, and plentiful hydrocarbon fluids. This study raises the exploration potential for MV TPb-Zn deposits in the Tethyan domain.