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Human activity causes increasing background concentrations of the greenhouse gases CO2 and O3. Increased levels of CO2 can be found in all terrestrial ecosystems. Damaging O3 concentrations currently occur over 29% of the world's temperate and subpolar forests but are predicted to affect fully 60% by 2100 (ref. 3). Although individual effects of CO2 and O3 on vegetation have been widely investigated, very little is known about their interaction, and long-term studies on mature trees and higher trophic levels are extremely rare. Here we present evidence from the most widely distributed North American tree species, Populus tremuloides, showing that CO2 and O3, singly and in combination, affected productivity, physical and chemical leaf defences and, because of changes in plant quality, insect and disease populations. Our data show that feedbacks to plant growth from changes induced by CO2 and O3 in plant quality and pest performance are likely. Assessments of global change effects on forest ecosystems must therefore consider the interacting effects of CO2 and O3 on plant performance, as well as the implications of increased pest activity.