Nitrogen fixation by cyanobacteria supplies critical bioavailable nitrogen to marine ecosystems worldwide; however, field and lab data have demonstrated it to be limited by iron, phosphorus and/or CO2. To address unknown future interactions among these factors, we grew the nitrogen-fixing cyanobacterium Trichodesmium for 1 year under Fe/P co-limitation following 7 years of both low and high CO2 selection. Fe/P co-limited cell lines demonstrated a complex cellular response including increased growth rates, broad proteome restructuring and cell size reductions relative to steady-state growth limited by either Fe or P alone. Fe/P co-limitation increased abundance of a protein containing a conserved domain previously implicated in cell size regulation, suggesting a similar role in Trichodesmium. Increased CO2 further induced nutrient-limited proteome shifts in widespread core metabolisms. Our results thus suggest that N2-fixing microbes may be significantly impacted by interactions between elevated CO2 and nutrient limitation, with broad implications for global biogeochemical cycles in the future ocean. Sample number sample description 1 380-1 2 380-2 3 380-3 4 750-1 5 750-2 6 750-3 7 380-1P 8 380-2P 9 380-3P 10 800-1P 11 800-2P 12 800-3P 13 380-1Fe 14 380-2Fe 15 380-3Fe 16 750-1Fe 17 750-2Fe 18 750-3Fe 19 380-1FeP 20 380-2FeP 21 380-3FeP 22 750-1FeP 23 750-2FeP 24 750-3FeP