Differential exhumation in the Puna Plateau and Eastern Cordillera of NW Argentina is controlled by inherited paleostructures and resulting paleotopography related to the Cretaceous Salta Rift paleomargins. The Cenozoic deformation front related to the development of the Andean retro-arc orogenic system is generally associated with >4 km of exhumation, which is recorded by Cenozoic apatite fission-track (AFT) and (U-Th-[Sm])/He ages (He ages) in the Eastern Cordillera of NW Argentina. New AFT ages from the top of the Nevado de Cachi document Oligocene (ca. 28 Ma) cooling, which, combined with existing data, indicates exhumation of this range between ca. 28 Ma and ca. 14 Ma. However, some of the highest ranges in the Eastern Cordillera preserve Cretaceous ages indicative of limited Cenozoic exhumation. Samples collected from an ∼3-km-elevation transect along the northern part of the Sierra de Quilmes paleorift flank (Laguna Brava) show AFT ages between ca. 80 and ca. 50 Ma and He ages between ca. 45 and ca. 10 Ma. Another set of samples from an ∼1-km-elevation transect farther to the southwest (La Quebrada) shows Cretaceous AFT ages between ca. 116 Ma and ca. 76 Ma, and mainly Cretaceous He ages, in agreement with AFT data. Analysis of existing AFT and He ages from the area once occupied by the Salta Rift reveals a pattern characterized by Cretaceous ages along paleorift highs and Cenozoic ages within paleorift hanging-wall basins and later foreland basin depocenters. This pattern is interrupted by the Sierras Pampeanas at ∼28°S, which record mid-Cenozoic ages. Our data are consistent with a complex inherited pattern of pre-Andean paleostructures, likely associated with paleotopography, which was beveled by the Cenozoic regional foreland basin and reactivated during the late Neogene (ca. <10 Ma), strongly controlling the magnitude of Cenozoic uplift and exhumation and thus cooling age distribution. This, combined with variable lithologic erodibility, resulted in an irregular distribution of themochronological ages.