Earth’s topography results from complex interactions between deep and surface processes operating on a range of spatio-temporal scales. To quantify the evolution of long-wavelength (>100 km) vertical motions caused by sub-plate support, for which generating sufficient geological observations is challenging, I combine novel approaches across global, continental and regional scales. In Chapter 2, I exploit a paleobiological database to generate a new compilation of >24,000 spot measurements of uplift across all continents. Records from western North America and eastern SouthAmerica are combined with geophysical observations and isostatic calculations to explore how litho-spheric thinning and mantle thermal anomalies may generate uplift of the observed wavelengths and amplitudes. In Chapter 3, the uplift inventory developed in Chapter 2 is augmented by additional stratigraphic markers and is subsequently used to estimate post-depositional uplift of the North American Continent. To bridge the gaps between these measurements, an inverse modelling scheme is used to calculate the smoothest spatio-temporal pattern of rock uplift rate that yields the smallest misfit between 4161 observed and calculated longitudinal river profiles. A landscape evolution model driven by this calculated rock uplift history is used to determine drainage patterns, denudation and sedimentary flux from Late Cretaceous times until present. These patterns are consistent with stratigraphic and thermochronologic observations. In Chapter 4, I combine geophysical observations and isostatic calculations with 27 backstripped wells in the Baltimore Canyon Trough to propose upper mantle drawdown produced ~600 m excess water-loaded subsidence between ~20–0 Ma. Using the landscape evolution model from Chapter 3, well data and published isopachs, I explore the contribution of source region uplift to increased Neogene basin-wide sediment accumulation. Results suggest the Middle Miocene sediments might not be sourced from the Appalachians, or models are too simplistic to predict the increased sedimentary flux.