The effects of a new hypothesis about mountain building in Greenland on ice sheet initiation are investigated using an ice sheet model in combination with a climate model. According to this hypothesis, low-relief landscapes near sea level characterised Greenland in Miocene times until two phases of km-scale uplift in the late Miocene and in the latest Miocene-Pliocene (beginning at 10 and ~. 5. Ma, respectively) initiated the formation of the present-day mountains. The topography of Greenland, prior to these uplift events is reconstructed from the present-day, isostatically compensated bedrock by mapping the two main steps in the landscape that resulted from the two uplift phases. Ice sheet initiation is studied using the topography before uplift and after each phase of uplift by applying different forcing conditions relevant for the late Cenozoic, which was characterised by long-term cooling superimposed by cold and warm excursions. The modelling results show that no ice initiates in the case of the low-lying and almost flat topography prior to the uplifts. However, the results demonstrate a significant ice sheet growth in response to the orographically induced increase in precipitation and the cooling of surface temperatures accompanying the uplift. Large amounts of ice are able to form after the first uplift event, but the ice sheet is sensitive to changes in climate. The results show that the second phase of uplift facilitates ice sheet build-up further and increases the stability of the ice sheet by providing anchoring points which are not available to the same extent in the lower topographies. However, the results also reveal a Föhn effect that inhibits ice sheet expansion into the interior Greenland and thus shifts the threshold of formation of inland ice towards colder temperatures. Under conditions that are colder than the present, the ice can overcome the Föhn effect, flow into the interior and form a coherent ice sheet. The results thus indicate that the Greenland Ice Sheet of today is a relict formed under colder conditions. The modelling results are consistent with the observed climatic variability superimposed on the general cooling trend in the late Cenozoic: e.g., ice rafted debris in late Miocene deposits off southeast Greenland and the mid-Pliocene Warmth. The late Cenozoic mountain building in Greenland augments the effects of the climatic deterioration leading to the Northern Hemisphere glaciations, and without the second phase of uplift, the Greenland Ice Sheet would have been more sensitive to the changes in climate over the past millions of years.