Fluid-inclusion studies of radiometrically dated (U/Pb, Th/Pb) calcite samples document the presence of hydrothermal fluids at ca. 251, 137, 67, and probably 39 Ma within the Tri-State Zn-Pb mining district of Missouri, Kansas, and Oklahoma. Fluid inclusions indicate minimum temperatures and equivalent salinities ranging from highs of 122 °C and 24 wt% NaCl ca. 251 Ma to lows of 52 °C and 0 wt% NaCl ca. 39 Ma. The two earliest calcites contain primary petroleum inclusions, but these are absent in samples younger than ca. 137 Ma. When combined with information on metal-rich shales, paleomagnetism, and modern groundwater flow, our results are most readily explained by periodic influxes of hydrothermal fluids of diverse compositions for >200 m.y. and sporadic migration of hydrocarbons for at least 100 m.y. in the southern Midcontinent.