The limits for stomatal conductance are set by stomatal size (SS) and density (SD). An inverse relationship between SS and SD has been observed in fossil and living plants. This has led to hypotheses proposing that the ratio of SS to SD influences the diffusion pathway for CO2 and degree of physiological stomatal control. However, conclusive evidence supportive of a functional role of the SS-SD relationship is not evident, and patterns in SS-SD may simply reflect geometric constraints in stomatal spacing over a leaf surface. We examine published and new data to investigate the potential functional significance of the relationship between SS and SD to atmospheric [CO2] in multiple generation adaptive responses and short-term acclamatory adjustment of stomatal morphology. Consistent patterns in SS and SD were not evident in fossil and living plants adapted to high [CO2] over many generations. However, evolutionary adaptation to [CO2] strongly affected SS and SD responses to elevated [CO2], with plants adapted to the 'low' [CO2] of the past 10 million years (Myr) showing adjustment of SS-SD, while members of the same species adapted to 'high' [CO2] showed no response. This may suggest that SS and SD responses to future [CO2] will likely constrain the stimulatory effect of 'CO2-fertilisation' on photosynthesis. Angiosperms generally possessed higher densities of smaller stomata that corresponded to a greater degree of physiological stomatal control consistent with selective pressures induced by declining [CO2] over the past 90 Myr. Atmospheric [CO2] has likely shaped stomatal size and density relationships alongside the interaction with stomatal physiological behaviour. The rate and predicted extent of future increases in [CO2] will have profound impacts on the selective pressures shaping SS and SD. Understanding the tradeoffs involved in SS-SD and the interaction with [CO2], will be central to the development of more productive climate resilient crops.