Research on the uplift history of the Sierra Nevada mountain range has yielded seemingly conflicting results. Some studies argue for substantial uplift within the past 3–5 m.y.; others suggest that high elevations may have existed since the Cretaceous. The rain shadow across the Sierra Nevada is associated with a strong isotopic gradient, with lower δ18O values in precipitation on the leeward side of the range. Reconstruction of the δ18O value of meteoric water as a monitor of paleoelevation has focused mainly on the leeward side of the Sierras, but interpretation of the results of these studies may be complicated by shifts in global climate and regional moisture sources. We address these concerns by analyzing the δ18O value of tooth enamel bioapatite from contemporaneous mammalian fossils on either side of the present Sierra range. By sampling across the range, δ18O differences induced by a rain shadow can be isolated from other complicating factors. Our results indicate that the Sierra rain shadow has existed since at least 16 Ma, which is an important constraint on models for the tectonic evolution of the western United States. Unfortunately, temporal resolution for localities is too coarse to differentiate between glacial and interglacial localities during the past 2 m.y., so we cannot evaluate if there was a latest Cenozoic pulse of uplift or elevation loss.