Reducing surface ozone (O₃) to concentrations in compliance with the national air quality standard has proven to be challenging, despite tighter controls on O₃ precursor emissions over the past few decades. New evidence indicates that isoprene emissions changed considerably from the mid-1980s to the mid-1990s owing to land-use changes in the eastern United States (Purves et al., 2004). Over this period, U.S. anthropogenic VOC (AVOC) emissions decreased substantially. Here we apply two chemical transport models (GEOS-CHEM and MOZART-2) to test the hypothesis, put forth by Purves et al. (2004), that the absence of decreasing O₃ trends over much of the eastern United States may reflect a balance between increases in isoprene emissions and decreases in AVOC emissions. We find little evidence for this hypothesis; over most of the domain, mean July afternoon (1300–1700 local time) surface O₃ is more responsive (ranging from −9 to +7 ppbv) to the reported changes in anthropogenic NO_x emissions than to the concurrent isoprene (−2 to +2 ppbv) or AVOC (−2 to 0 ppbv) emission changes. The estimated magnitude of the O₃ response to anthropogenic NO_x emission changes, however, depends on the base isoprene emission inventory used in the model. The combined effect of the reported changes in eastern U.S. anthropogenic plus biogenic emissions is insufficient to explain observed changes in mean July afternoon surface O₃ concentrations, suggesting a possible role for decadal changes in meteorology, hemispheric background O₃, or subgrid-scale chemistry. We demonstrate that two major uncertainties, the base isoprene emission inventory and the fate of isoprene nitrates (which influence surface O₃ in the model by −15 to +4 and +4 to +12 ppbv, respectively), preclude a well-constrained quantification of the present-day contribution of biogenic or anthropogenic emissions to surface O₃ concentrations, particularly in the high-isoprene-emitting southeastern United States. Better constraints on isoprene emissions and chemistry are needed to quantitatively address the role of isoprene in eastern U.S. air quality.