Giant foxtail putatively resistant to acetolactate synthase (ALS) inhibitors has been reported widely in the upper Midwest, typically in fields with a history of ALS inhibitor use in continuous corn or corn–soybean rotation. However, it is not known whether these giant foxtail populations vary in their response to ALS inhibitors. Therefore, our objectives were to confirm and quantify resistance of giant foxtail accessions from Wisconsin, Minnesota, and Illinois to imidazolinone and sulfonylurea herbicides; to determine the mechanism of resistance; and to determine the mechanism of resistance inheritance. Dose–response experiments using three- to four-leaf stage giant foxtail plants in the greenhouse confirmed cross-resistance of the Wisconsin, Minnesota, and Illinois accessions to imazethapyr and nicosulfuron. Based on ED50 values (the effective dose that reduced shoot dry biomass by 50% compared to the nontreated plants), the Wisconsin, Minnesota, and Illinois accessions were 16-, 17-, and 15-fold resistant to imazethapyr, respectively, and 21-, 19-, and 9-fold resistant to nicosulfuron, respectively, compared to susceptible accessions. In contrast, all accessions were susceptible and responded similarly to fluazifop-P. Based on an in vivo ALS assay, the Wisconsin, Minnesota, and Illinois accessions were > 750-, > 320-, and > 670-fold resistant to imazethapyr, respectively, and 1,900-, > 1,900-, and 80-fold resistant to nicosulfuron, respectively, compared to susceptible accessions. To determine the inheritance of resistance traits, hybrid F1 families were generated from crosses between ALS inhibitor–susceptible and -resistant plants from Minnesota. Three distinct plant phenotypes—resistant (R), intermediate (I), and susceptible (S)—were identified in the F2 generation following exposure to imazethapyr. In repeated experiments, these phenotypes segregated in a 1:2:1 (R:I:S) ratio, indicative of a trait associated with a single, nuclear, semidominant allele.