Ongoing human-induced changes in the composition of the atmosphere continue to stimulate interest in the effects of high CO2 on plants, but its potential impact on inducible plant defense pathways remains poorly defined. Recently, several studies have reported that growth at elevated CO2 is sufficient to induce defenses such as the salicylic acid pathway, thereby increasing plant resistance to pathogens. These reports contrast with evidence that defense pathways can be promoted by photorespiration, which is inhibited at high CO2. Here, we review signaling, metabolic, and redox processes modulated by CO2 levels and discuss issues to be resolved in elucidating the relationships between primary metabolism, inducible defense, and biotic stress resistance.