New tectonic field data and paleostress determinations in the Eastern Cordillera of Colombia enable us to identify stress regimes that prevailed in the northern Andes since Late Cretaceous times until present day. These regimes were characterized by an E-W to WSW-ENE active contraction from Late Cretaceous to late Paleocene. This direction subsequently changed to NW-SE and finally became WNW-ESE during the Andean tectonic phase. The characteristics and relative chronology of these regimes were deduced from field structures and stratigraphic criteria, using stress inversion of fault slip data sets. To evaluate our model, we used the rotation poles of the South America, Caribbean and Nazca plates relative to North America, and paleogeographic reconstructions of the Caribbean region to derive a kinematic model of the northern Andes. Assuming a general correspondence between the regional convergence directions and the regional compression, we built a theoretical model of the regional stress regimes based on kinematics of the northwestern South America since Late Cretaceous times. This model reveals a major variation at the end of the Paleocene when relative divergence shifted to convergence between the Americas. This is in agreement with our tectonic model based on independent tectonic field data inversion in the Eastern Cordillera. This regional kinematic and tectonic change, which affected the Caribbean at the end of the Paleocene, was responsible for, and consistent with, the major change in stress patterns and structural style in the Eastern Cordillera. It is also coeval with the development of a major regional unconformity in Colombia.