ABSTRACT Natural fractures are abundant in the Vaca Muerta Formation and are important because they may affect hydraulic-fracture growth during well stimulation. They contribute to anisotropic mechanical behavior of the reservoir rock and may cause hydraulic fractures to arrest or divert along them by opening or shear. In the subsurface, the Vaca Muerta Formation contains bed-parallel veins (BPV) of fibrous calcite (beef) and bed-perpendicular, completely or partly calcite-filled, opening-mode fractures in multiple orientations. In outcrops of the Vaca Muerta Formation in the Agrio fold-and-thrust belt, BPV and bed-perpendicular fractures are also common. Fracture cement geochemistry (including stable isotopes) and fluid inclusion and clumped isotopic thermometry indicate that the outcrops are similar to the most mature parts of the Vaca Muerta reservoir and can be used as guides for this part of the basin. In outcrops near the Cerro Mocho area, two main bed-perpendicular, opening-mode fracture sets are oriented east–west (oldest) and north–south (youngest), and two additional sets (northeast–southwest and northwest–southeast) are locally present. Fluid inclusion microthermometry, combined with burial-history curves, indicates that BPV in the area of Loncopué formed in the Late Cretaceous during bed-parallel contraction and in overpressure conditions, whereas bed-perpendicular sets formed in the Paleocene. Similar ages were obtained for Puerta Curaco outcrop on the basis of clumped isotope temperatures, although BPV opening may have lasted until the Miocene in this area. BPV are the most common and some of the oldest types of fracture sampled by vertical cores, and stable isotope analyses indicate that they formed deep in the subsurface, probably under conditions similar to those inferred for outcrops. In cores of the Loma Campana block, bed-perpendicular fractures show orientations similar to those in outcrops, although the youngest, north–south set is generally missing. Without appropriate fluid inclusions for microthermometry or oriented cross-cutting relationships in core, fracture timing was established on the basis of a tectonic model. Our model indicates that in the Loma Campana block, fractures preferentially formed in east–west and northeast–southwest orientations in the Early Cretaceous, northeast–southwest in the Late Cretaceous, northwest–southeast in the Cenozoic, and east–west and east-northeast–west-southwest at present. Fracture timing and orientations from this tectonic model, fracture aperture from core, fracture height and length measured in outcrop, and fracture intensity from a geomechanical model calibrated with core and image logs were used to construct discrete fracture network (DFN) models of the subsurface and build specific reservoir development plans.