In the central Appalachians, fluid inclusion microthermometry and oxygen and carbon stable isotope analysis vein minerals from the Middle Devonian shale section show that fluid conditions (pressure, temperature, and composition) are constantly changing during deformation and vary spatially across the fold-thrust belt. The earliest fractures in the region formed prior to folding, early during the Alleghenian orogeny as the rocks were buried into the oil generation window. They contain minerals that contain degraded hydrocarbon inclusions and basinal brine inclusions. During multiple vein reopening events, later mineral stages contain increasingly more mature hydrocarbon fluids. Late quartz mineralization is pervasive and typically contains the high-temperature brine inclusions. The vein opening history is related to changes in fluid connectivity associated with (1) burial by over-thrusting and/or syntectonic depositional loading and/or (2) folding during uplift and erosion. Initial fracture formation and fluid-trapping depths range from 3.5 km (2.2 mi) in the Plateau province and along the Appalachian structural front to 4.5 to 5.0 km (2.8 to 3.1 mi) in the Valley and Ridge province. Late-stage fracturing and fracture reopening is related to the maximum syntectonic burial, which varies from about 4 km (2.5 mi) in the Plateau to over 11 km (6.8 mi) in the Valley and Ridge. Fractures in the Valley and Ridge and western Pennsylvania Plateau provinces cannot be categorized into the simple J(1) and J(2) classification model. Burial history modeling indicates that fractures forming within and near the end of the oil window were NNW- and NW-striking, not ENE-striking, J(1) fractures.