The fractionation of stable Li isotopes ( 6 Li, 7 Li) has become a promising proxy for assessing changes related to continental silicate weathering patterns. Recently, the first complete record of Cenozoic seawater Li isotopic composition (δ 7 Li) was reported (Misra and Froelich, 2012, Science 335, 818–821) showing a stepwise increase of +9‰ over the last 56Ma. This increase was attributed to a general change in continental silicate weathering behavior caused by tectonic uplift. In particular, the low global average riverine δ 7 Li inferred for the Paleocene–Eocene boundary was explained by congruent silicate weathering of primary silicate minerals, which is inconsistent with the stoichiometry of secondary minerals and the resultant water chemistry.In this study, we present a novel reactive transport modeling approach that explicitly includes Li isotopic fractionation to assess alternative geochemically-constrained interpretations that do not rely on congruent weathering. Simulations show that riverine δ 7 Li is mainly controlled by the subsurface residence time, the corresponding weathering intensity, and the concentration of a river's suspended load. Based on these factors, we suspect that the low δ 7 Li observed at the Paleocene–Eocene boundary was inherited from a high weathering intensity with predominant weathering of previously formed secondary mineral phases (e.g., clays, oxides) having low δ 7 Li values. Moreover, we conclude that the Cenozoic δ 7 Li increase was caused by an increasing amount of primary silicate mineral dissolution inherited from an increasing suspended river load concentration and a decreasing weathering intensity both likely induced by tectonic uplift. In contrast, Cenozoic cooling and corresponding pCO 2 and precipitation variations do not seem to have a distinct control on the Cenozoic δ 7 Li record.Finally, our simulations revealed a close relation between δ 7 Li and CO 2 consumption by silicate weathering implying that the Cenozoic seawater δ 7 Li record could be potentially used to quantify such CO 2 consumption through time. However, more experimental and modeling work is required to quantify the correlation between seawater δ 7 Li and global CO 2 consumption by silicate weathering. Key parameters are the temperature-dependent thermodynamic properties of specific Li-bearing primary and secondary minerals (e.g., crystallographic Li substitution reaction, maximum Li substitution, Li solubility, Li isotopic fractionation factor) as well as the determination of global average subsurface and river discharges through time.