In the central Andes, giant porphyry copper deposits of similar ages group into discrete geographic clusters that are regularly spaced and aligned within orogen-parallel belts. This clustering highlights how exceptional geologic processes affected localized regions of the lithosphere during mineralization and that the spatial and temporal distribution of giant porphyry deposits is nonrandom. Development of favorable regions of lithosphere for significant metal concentration are linked to the overlap of structural pathways that focus fluid and magma flow from the mantle to upper crust during high-horizontal-compressive-strain events. These structural pathways are notoriously difficult to identify in the field due to their often-subtle surficial manifestations and continental scale. Field mapping at multiple scales in northwest Argentina and southern Peru, as well as regional structural traverses throughout the central Andes, indicates the presence of regional-scale structural corridors 5 to 25 km wide and hundreds of km long that consist of myriad fault planes. The variable width and diffuse surface expression of these corridors is interpreted to reflect the upward propagation of underlying zones of basement weakness through younger supracrustal sequences in the overriding plate. Such structural corridors are (1) apparent at multiple scales of investigation, (2) long-lived, (3) preferentially reactivated though time, and (4) evident in geophysical data sets. This structural architecture formed in response to the interplay of pre-Cenozoic tectonics and the orientation of inherited structural weaknesses. These fault systems persist in the upper crust as steep zones of enhanced permeability that can preferentially reactivate as pathways for ascending hydrous magmas and fluids during major deformation events. Linear orogen-parallel structural belts cogenetic with the magmatic arc provide the first-order control to giant porphyry copper deposit distribution. The second-order control is the intersection of orogen-oblique structural corridors with the orogen-parallel belts, localizing deposit clusters at these intersections. Such regions are inferred to have been zones of deep permeability, with vertical translithospheric pathways activated during high-strain tectonic events that affected the intra-arc stress field.