The timing, rates, and spatial patterns of elevation change in the Sierra Nevada, California, USA, have long been the subject of vigorous debate owing to their importance in constraining the tectonic history of western North America and models of orogenesis. Here we present a systematic analysis of multiple measures of fluvial geomorphology along the entire length of the range and interpret these observations using 1-D and 2-D landscape evolution modeling based on the stream power fluvial erosion rule with the rate parameter calibrated from a large data set of millennial-scale erosion rates. We demonstrate that westward-draining rivers in the Sierra Nevada are in a disequilibrium state and that this state is consistent with the transient fluvial response expected from significant down-to-the-west tilting in the last 11 m.y. Assuming rigid-block tilting and using multiple independent measures of tilt magnitude, we find that the magnitude of surface uplift from late Cenozoic tilting appears to have been similar along strike and likely resulted in ~500–1300 m of surface uplift at the crest (0.3–0.8° tilt) from the Yuba through the Stanislaus rivers (~39.2–38.2°N) and 1000–1400 m of surface uplift at the crest (0.6–0.9° tilt) from the Tuolumne River south through the Kings River (~38.2–36.4°N). We show that the transient fluvial response to tilting in the northern Sierra is heavily modulated by heterogeneous lithology and drainage area exchange in a manner that reconciles the high spatial variability in basement incision observed in numerous prior studies. However, we find that heterogeneous lithology alone cannot explain both the transient state and observed patterns in channel steepness, which seem to require late Cenozoic changes in tectonic forcing. Beyond the regional implications of a short-lived rapid pulse of late Cenozoic surface uplift along the entire length of the range, our results demonstrate that a range-wide approach in which river networks are analyzed both in planform and profile can elucidate tectonic histories despite heterogeneous lithology and ongoing changes in network topology.