Abstract Transgenic corn and cotton produce crystalline (Cry) proteins derived from the soil bacterium Bacillus thuringiensis (Bt) that are toxic to lepidopteran larvae. Helicoverpa zea, a key pest of corn and cotton in the U.S., has evolved widespread resistance to these proteins produced in Bt corn and cotton. While the genomic targets of Cry selection and the mutations that produce resistant phenotypes are known in other lepidopteran species, little is known about how Cry proteins shape the genome of H. zea . We scanned the genomes of Cry1Ac-selected and unselected H. zea lines, and identified eleven genes on six scaffolds that showed evidence of selection by Cry1Ac, including cadherin-86C ( cad-86C ), a gene from a family that is involved in Cry1A resistance in other lepidopterans. Although this gene was expressed in the H. zea larval midgut, the protein it encodes has only 17 to 22% identity with cadherin proteins from other species previously reported to be involved in Bt resistance. An analysis of midgut-expressed cDNAs showed significant between-line differences in the frequencies of putative nonsynonymous substitutions (both SNPs and indels). Our results indicate that cad-86C is a target of Cry1Ac selection in H. zea . Future work should investigate phenotypic effects of these nonsynonymous substitutions and their impact on phenotypic resistance in field populations.