Technical Abstract: Determining plant response at the biochemical/physiological level to a changing global environment is a prerequisite for constructing accurate models to predict plant productivity. High temperature and CO2 impact plant biomass accumulation by altering the rate of net photosynthesis such that the measured rates differ greatly from the potential rates predicted from commonly used models. Such models are based on assumptions pertaining to biochemical limitations to net photosynthesis by the capacity of ribulose-I.5-bisphosphate carboxylase/oxygenase (Rubisco). the enzyme that ultimately limits the rate of photosynthetic CO2 fixation in C3 and C4 plants, or the capacity of electron transport to supply energy for Calvin cycle activity. Here we provide evidence that the impact of high temperature and CO2 on net photosynthesis can be accurately calculated from predictive models based solely on Rubisco kinetics if the modeled rate of photosynthesis is adjusted for heat and CO2-induced changes in the activation state of Rubisco. The activation state of Rubisco, which is regulated by the activity of Rubisco activase, thus appears to be the primary limitation to net photosynthesis at high temperature and/or CO2, This limitation to net photosynthesis has not been incorporated into common biochemical models, thus compromising their effectiveness. The expression of activase mRNA was not indicative of the central role of activase in the response of photosynthesis to high temperature thus revealing limitations of using a broad genomics approach to identify the impact of environmental stress on plant metabolism.