The long-term evolution of the East Greenland fjord region is investigated using geomorphological and stratigraphical evidence to: (1) assess the nature of landscape modification caused by late Cenozoic ice sheet glaciation; and (2) relate patterns of glacial landscape modification to first-order (i.e. continent-margin scale) topography and geology. Geomorphological and stratigraphical evidence demonstrates evolution of the first-order topography and incision of at least part of the present first-order fjord system by not, vert, similar 55 Ma. This hypothesis is tested using apatite (U–Th)/He ages for samples from two bedrock profiles near Kong Oscar Fjord. The thermochronology supports landscape evolution before 55 Ma, followed by relative tectonic stability, because it indicates rapid denudation around the time of rifting that occurred prior to continental breakup (i.e. between not, vert, similar 75 and 55 Ma). The nature of landscape modification caused by late Cenozoic glacial erosion appears to have been controlled by first-order topography and geology, with selective ice sheet erosion in areas of high-elevation Caledonian basement and apparently little glacial erosion of low-elevation Mesozoic sedimentary strata. Nevertheless, fjord morphometry demonstrates systematic evolution of the first-order fjord system from confined and overdeepened fjords in Caledonian basement to wider and disproportionately larger fjords in Mesozoic strata. The latter indicates that changes in lithological strength enabled the development of more efficient fjord morphology under full glacial conditions that may have promoted fast ice flow.