The rate of CO2 assimilation by plants is directly influenced by the concentration of CO2 in the atmosphere, ca. As an environmental variable, ca also has a unique global and historic significance. Although relatively stable and uniform in the short term, global ca has varied substantially on the timescale of thousands to millions of years, and currently is increasing at seemingly an unprecedented rate. This may exert profound impacts on both climate and plant function. Here we utilise extensive datasets and models to develop an integrated, multi-scale assessment of the impact of changing ca on plant carbon dioxide uptake and water use. We find that, overall, the sensitivity of plants to rising or falling ca is qualitatively similar across all scales considered. It is characterised by an adaptive feedback response that tends to maintain 1 − ci/ca, the relative gradient for CO2 diffusion into the leaf, relatively constant. This is achieved through predictable adjustments to stomatal anatomy and chloroplast biochemistry. Importantly, the long-term response to changing ca can be described by simple equations rooted in the formulation of more commonly studied short-term responses.