Diclofop-resistant Italian ryegrass is widespread in southwestern North Carolina, and growers have resorted to using acetolactate synthase (ALS) inhibitors such as mesosulfuron and pyroxsulam to control this weed in wheat. In the spring of 2007, mesosulfuron failed to control Italian ryegrass in several wheat fields. Seed were collected from six fields in two counties and greenhouse studies were conducted to determine response to mesosulfuron and the acetyl-CoA carboxylase (ACCase) inhibitors diclofop and pinoxaden. All populations were resistant to diclofop and cross-resistant to pinoxaden. Five of the six populations were resistant to diclofop, pinoxaden, and mesosulfuron. An additional study with two biotypes confirmed cross-resistance to the ALS inhibitors imazamox, mesosulfuron, and pyroxsulam. Resistance to mesosulfuron was heritable.