The Vaca Muerta Formation consist of outer ramp to basinal facies in a mixed siliciclastic–carbonate creating an organic-rich section up to 500 m thick. This chapter documents stratal terminations, main bounding surfaces, and stacking patterns of the Vaca Muerta–Quintuco system as a means to establish a new sequence stratigraphic framework. The data set comprises more than 500 wells and a basin-scale seismic coverage that spans 30,000 km² Regional seismic interpretations and well correlations were calibrated with well geochemical data and acoustic impedance seismic sections. Twelve high-frequency depositional sequences (HFS) with variable combinations of systems tracts were defined and grouped in three low-frequency depositional sequences (LFS). Within this sequence stratigraphic framework, the Vaca Muerta Formation includes organic-rich (total organic carbon, TOC > 2wt. %) and organic-poor intervals (TOC < 2wt. %) At a high-frequency scale, the organic-rich intervals with the highest concentration of TOC belong to transgressive systems tracts and the lower sections within clinoform bottomset and foreset of highstand systems tracts. These condensed sections usually show the best reservoir properties in the self-sourced unconventional play. Conversely, organic-poor intervals are found in the foresets of falling-stage systems tracts and lowstand systems tracts. Condensed sections of each sequence allow subdivide the unconventional play in a stacking of 12 organic-rich Vaca Muerta units (OVM, TOC ≥ 2wt. %). The lowermost eight OVM units correspond to the main tested landing zones. Moreover, a detailed map of shelf breaks reveals a strong three-dimensional (3-D) spatial variability, which is summarized in four groups of plan-view geometries. The 3-D spatial variability of the organic-rich intervals is analyzed at local scale in two cases with different plan-view geometries. At regional scale, thickness maps of the main OVM units allow infer stratigraphic controls (e.g., systems tracts, previous clinoform paleo-topography) and tectonic controls, both regional (morphostructural domains) and local (subsidence axes and paleo-highs), active during the deposition of the Vaca Muerta Formation. The proposed sequence stratigraphic framework provides a predictive understanding of 3-D spatial distribution of the organic-rich intervals in subsurface assessments for the Vaca Muerta play and is applicable to the exploration of other analogous (mixed siliciclastic-carbonate systems) self-sourced unconventional resources.