Debate surrounds the origin, uplift, and evolution of the northern Sierra Nevada and western Basin and Range. The studies presented here integrate different scales of observation, from local paleovalley morphology, estimation of local slopes, and braided stream alluvial architecture, to regional assessments of sediment and volcanic provenance and paleoelevations across the proposed ancestral Sierra Nevada–Nevadaplano to gain a better understanding of early Cenozoic topography, morphology, and landscape evolution of the region, and to assess the possible tectonic and climatic drivers for that evolution. Results from sedimentologic analysis of Eocene fluvial deposits show diachronous, localized paleovalley incision and braided stream aggradation in a system influenced by Eocene climate, eustasy, and Laramide tectonism, and suggest that previous estimates of the timing and amount of range uplift based on paleochannel gradients may be invalid. Overlying Oligocene ignimbrites deposited in the Sierra Nevada were geochemically and geochronologically correlated to sources in central Nevada, and results from this work show that ignimbrites traveled over 200 km from their source calderas across what is now the crest of the Sierra Nevada, and that in the Oligocene, no drainage divide existed between Nevada source calderas and sample locations 200 km west. Hydrated volcanic glass from these units was used as a proxy for the isotopic composition (δD) of Oligocene meteoric water, which reflects the effect of ancient topography on precipitation. δD decreases from west to east across the Sierra Nevada by ∼48‰, which is similar to the isotopic gradient of precipitation over the area today. δD across Nevada decreases at a significantly lower gradient, reflecting a significant reduction in the rate of increase of paleoelevation with distance, and may reflect a gradual increase in mean elevation from west to east or partially closed system hydrology. This multidisciplinary approach provides both a detailed reconstruction of the evolution of the ancestral Sierra Nevada drainage system from Eocene to Oligocene time and multiple lines of evidence to support the conclusion that the northern Sierra Nevada likely acted as the steep western flank of a gradually sloping high-elevation plateau (“Nevadaplano”) in the Oligocene. Miocene to Holocene extension lowered elevations across what is now the Basin and Range, possibly associated with gravitational spreading of overthickened, magmatically and radiogenically heated crust.