The approximately N-S–trending Andean retroarc fold-and-thrust belt is the locus of up to 300 km of Cenozoic shortening at the convergent plate boundary where the Nazca plate subducts beneath South America. Inherited pre-Cenozoic differences in the overriding plate are largely responsible for the highly segmented distribution of hydrocarbon resources in the fold-and-thrust belt. We use an ~7500-km-long, orogen-parallel (“strike”) structural cross section drawn near the eastern terminus of the fold belt between the Colombia-Venezuela border and the south end of the Neuquén Basin, Argentina, to illustrate the control these inherited crustal elements have on structural styles and the distribution of petroleum resources. Three pre-Andean tectonic events are chiefly responsible for segmentation of sub-basins along the trend. First, the Late Ordovician “Ocloyic” tectonic event, recording terrane accretion from the southwest onto the margin of South America (present-day northern Argentina and Chile), resulted in the formation of a NNW-trending crustal welt oriented obliquely to the modern-day Andes. This paleohigh influenced the distribution of multiple petroleum system elements in post-Ordovician time. Second, the mid-Carboniferous “Chañic” event was a less profound event that created modest structural relief. Basin segmentation and localized structural collapse during this period set the stage for deposition of important Carboniferous and Permian source rocks in the Madre de Dios and Ucayali Basins in Peru. Third, protracted rifting that lasted throughout the Mesozoic provided the framework for deposition of many of the source rocks in the Subandean belt, but most are not as widely distributed as the Paleozoic sources in Bolivia and Peru. We attribute variations in the style of Andean deformation and distribution of oil versus gas in the Subandes largely to differences in pre-Cenozoic structure along the fold belt. The petroleum occurrences and remaining potential can be understood in the context of three major geographic subdivisions of the Subandes. Between Colombia and central Peru, rich, late postrift Cretaceous source rocks occur beneath Upper Cretaceous–Cenozoic strata that vary significantly in thickness, yielding large accumulations around the Cusiana field in Colombia and within the Oriente Basin in Ecuador, but weak or nonviable petroleum systems elsewhere, where the cover is too thin or too thick. The central Subandes of southern Peru and Bolivia evaded significant Mesozoic rifting, which kept Paleozoic sources shallow enough to delay primary or secondary hydrocarbon generation. After post-Oligocene propagation of the fold belt, however, numerous accumulations were formed around Camisea, Peru, and in the Santa Cruz–Tarija fold belt of central Bolivia. In the southern Subandes of Argentina, Paleozoic crustal thickening caused by terrane accretion and associated arc magmatism created a tectonic highland that precluded deposition and/or destroyed the effectiveness of any Paleozoic source rocks. Here, all accumulations in the foreland and in the fold belt rely on Triassic and younger source rocks deposited in both lacustrine and marine environments within narrow rifts. The trap styles and structurally restricted source rocks in the southern segment have yielded a much smaller discovered conventional resource volume than in the northern and central Subandean segments. In comparing the Subandean system to other global fold belt petroleum systems, it is undoubtedly the rule rather than the exception that the robustness of hydrocarbon systems varies on a scale of a few hundred kilometers in the strike direction. Our work in the Andes of South America suggests that this is because most continents possess heterogeneous basement, superposed deformation, and subbasin stratigraphy that vary on roughly this length scale.