C4 plants like maize (Zea mays) and sorghum (Sorghum bicolor) have a more efficient photosynthesis than C3 plants such as wheat (Triticum aestivum) and rice (Oryza sativa) due to a CO2-concentrating mechanism (CCM). How this CCM and the performance of C4 plants are impacted by space travel is unknown. We propose to compare the impact of space-station conditions on C3 and C4 metabolism using Brachypodium (Brachypodium distachyon) and Setaria (Setaria viridis) as model systems for C3 and C4 plants, respectively, and develop models that describe the molecular mechanisms for how C3 and C4 metabolisms are reprogrammed in the space environment compared to Earth. The obtained information would provide fundamental knowledge about C3 and C4 metabolism in space and could also be leveraged for evaluating the potential for growing small-stature cereal and vegetable C4 crops like foxtail millet (Setaria italica) and Amaranthus sp. for biogenerative support in future space explorations.