Elevated levels of atmospheric carbon dioxide (CO2), a consequence of anthropogenic global change, can profoundly affect the interactions between crop plants and insect pests and may promote yet another form of global change: the rapid establishment of invasive species. Elevated CO2 increased the susceptibility of soybean plants grown under field conditions to the invasive Japanese beetle (Popillia japonica) and to a variant of western corn rootworm (Diabrotica virgifera virgifera) resistant to crop rotation by down-regulating gene expression related to defense signaling [lipoxygenase 7 (lox7), lipoxygenase 8 (lox8), and 1-aminocyclopropane-1-carboxylate synthase (acc-s)]. The down-regulation of these genes, in turn, reduced the production of cysteine proteinase inhibitors (CystPIs), which are specific deterrents to coleopteran herbivores. Beetle herbivory increased CystPI activity to a greater degree in plants grown under ambient than under elevated CO2. Gut cysteine proteinase activity was higher in beetles consuming foliage of soybeans grown under elevated CO2 than in beetles consuming soybeans grown in ambient CO2, consistent with enhanced growth and development of these beetles on plants grown in elevated CO2. These findings suggest that predicted increases in soybean productivity under projected elevated CO2 levels may be reduced by increased susceptibility to invasive crop pests.