This study contributes to the uplift history of the Andes, which has received increasing attention in recent years because of its implications for geodynamic models and climate feedbacks. Shortening resulting in crustal thickening and removal of gravitationally unstable mantle lithosphere has been proposed to control deformation and uplift of Cordillera-type orogenic systems such as the Puna Plateau of the central Andes and its eastern margin, the Eastern Cordillera. We present new clumped isotope (Δ 47 ), δ 18 O, and δ 2 Η data from carbonate nodules, marlstone, spring deposits, and volcanic ashes from the Puna Plateau and Eastern Cordillera of NW Argentina. When combined with other geological evidence, our data indicate that the Puna Plateau was near its present elevation since at least~10 Ma, whereas the Eastern Cordillera rosẽ 1.5 km between~14 and~7 Ma. This history of uplift correlates with active shortening in the Eastern Cordillera and with incorporation of a regional foreland into the propagating orogenic wedge. Our study suggests that the elevation of the Puna Plateau changed little during the Miocene-Pliocene, whereas the margin experienced significant uplift associated with active deformation and crustal thickening.