There is evidence that increasing CO2 concentrations have reduced evapotranspiration and increased runoff through reductions in stomatal conductance during the twentieth century. While this process will continue to counteract increased evapotranspiration associated with future warming, it is highly dependent upon concurrent changes in photosynthesis, especially due to CO2 fertilization, nitrogen limitation, and ozone exposure. A new version of the Terrestrial Ecosystem Model (TEM-Hydro) was developed to examine the effects of carbon and nitrogen on the water cycle. We used two climate models (NCAR CCSM3 and DOE PCM) and two emissions scenarios (SRES B1 and A2) to examine the effects of climate, elevated CO2, nitrogen limitation, and ozone exposure on the hydrological cycle in the eastern United States. While the direction of future runoff changes is largely dependent upon predicted precipitation changes, the effects of elevated CO2 on ecosystem function (stomatal closure and CO2 fertilization) increase runoff by 3–7%, as compared to the effects of climate alone. Consideration of nitrogen limitation and ozone damage on photosynthesis increases runoff by a further 6–11%. Failure to consider the effects of the interactions among nitrogen, ozone, and elevated CO2 may lead to significant regional underestimates of future runoff.