The commonly observed extension in areas of elevated and thickened crust is an expected consequence of having excess gravitational potential energy (GPE) compared to the low GPE of the surrounding crust. While this conceptual model is well founded, it is less clear how well GPE-related stress orientations compare quantitatively to observed stress and strain rate orientations and what any inconsistency tells us about the presence of other competing forces. We estimate the GPE distribution for the central Andes and the greater Colorado Plateau area using topography and crustal thickness variations, respectively, and compare the related stress fields with the World Stress Map as well as with a geodetic strain rate field (for the Colorado Plateau only). In both areas, deviatoric stresses associated with GPE variations alone cannot fully account for the observed deformation rate field. For the central Andes only a combination of deviatoric stresses associated with GPE and relative plate motions can account for the near N–S tensional stress observed in the Peruvian Andes and the margin–normal compressional stress along the eastern Cordillera and sub-Andean fold-and-thrust belt. The observed deformation field around the Colorado Plateau shows E–W extension, largely inconsistent with the deviatoric stresses associated with GPE variations except for the area east of the Rio Grande Rift. The NE–SW oriented stress observed on the southwestern Colorado Plateau is consistent with the orientations of tensional deviatoric stresses associated with GPE variations. We argue that this consistency could be haphazard; stress observations may not reflect the current state of stress due to inherited structure, or could result from the relative high strength of Colorado Plateau that allows for regional GPE variations (and possibly basal shear) to be more significant forces than far-field plate interactions. For the central Andes and Colorado Plateau, stresses associated with GPE variations have a strong influence on the total stress field, and can thus be used to calibrate the overall level of deviatoric stress acting within the lithosphere.