The Southern Peninsula of Haiti is a seismically active east-west trending transpressive mountain range with elevations over 2 km. Present-day deformation is mainly partitioned along the left-lateral Enriquillo-Plantain Garden Fault Zone (EPGFZ) and associated oblique reverse faults and/or folds. The configuration of these faults, their respective timing, and the role of structural heritage on their development is poorly understood. To address these questions we present the results of extensive field campaigns, combined with satellite imagery interpretation and published data, which allows us to constrain the Cenozoic evolution of the Southern Peninsula. Our results show a polyphase tectonic history consisting of three major tectonic events: 1) Maastrichtian to early Paleocene crustal-scale folding that developed coevally with predominantly north to northeast dipping thrusts, resulting in uplift and erosion of the Cretaceous sedimentary cover in large parts of the Southern Peninsula. 2) Early Miocene uplift and erosion, which was strongest in the southwestern part of the peninsula and decreased eastwards, did not affect the Massif de la Selle. Uplift is most likely unrelated to strike-slip activity but resulted from folding in response to NE-SW shortening that possibly reactivated older, predominantly N-to NE-dipping thrusts. 3) Late Miocene to present-day deformation and uplift. Spatially distributed strike-slip started during the late Miocene and became progressively focused along the EPGFZ in the latest Miocene. Oblique and thrust faults locally postdate strike-slip activity from the Pliocene onward. Increase in compressional deformation from west to east is reflected by a change in structural style, with predominantly strike-slip faults in the west and transpressional faults in the east, the latter possibly rooted on the EPGFZ at depth. Paleo-stresses associated with a strikeslip regime are at a significantly high angle to the trace of the EPGFZ, indicating that the EPGFZ is a mechanically weak fault.