To evaluate whether anatectic and/or highly fractionated lithophile element-enriched rhyolite tuffs deposited in arid lacustrine basins lose enough lithium during eruption, lithification, and weathering to generate significant Li brine resources, pre-eruptive melt compositions, preserved in inclusions, and the magnitude of post-eruptive Li depletions, evident in host rhyolites, were documented at six sites in the western United States. Each rhyolite is a member of the bimodal basalt-rhyolite assemblage associated with extensional tectonics that produced the Basin and Range province and Rio Grande rift, an evolving pattern of closed drainage basins, and geothermal energy or mineral resources. Results from the 0.8 Ma Bishop tuff (geothermal) in California, 1.3 to 1.6 Ma Cerro Toledo and Upper Bandelier tephra (geothermal) and 27.9 Ma Taylor Creek rhyolite (Sn) in New Mexico, 21.7 Ma Spor Mountain tuff (Be, U, F) and 24.6 Ma Pine Grove tuff (Mo) in Utah, and 27.6 Ma Hideaway Park tuff (Mo) in Colorado support the following conclusions. Melt inclusions in quartz phenocrysts from rhyolite tuffs associated with hydrothermal deposits of Sn, Mo, and Be are extremely enriched in Li (1,000s of ppm); those from Spor Mountain have the highest Li abundance yet recorded (max 5,200 ppm, median 3,750 ppm). Forty-five to 98% of the Li present in pre-eruptive magma was lost to the environment from these rhyolite tuffs. The amount of Li lost from the small volumes (1–10 km3) of Li-enriched rhyolite deposited in closed basins is sufficient to produce world-class Li brine resources. After each eruption, meteoric water leaches Li from tuff, which drains into playas, where it is concentrated by evaporation. The localized occurrence of Li-enriched rhyolites may explain why brines in arid lacustrine basins seldom have economic concentrations of Li. Considering that hydrothermal deposits of Sn, Mo, Be, U, and F may indicate potential for Li brines in nearby basins, we surmise that the world’s largest Li brine resource in the Salar de Uyuni (10 Mt) received Li from nearby rhyolite tuffs in the Bolivian tin belt.