Littleseed canarygrass is a major weed of winter-season crops, although it is most dominant in wheat-growing regions in the Indo-Gangetic Plains of India, Pakistan, Nepal, and Bangladesh. Resistance in this species to photosystem II–inhibiting herbicide isoproturon was first recorded in 1992, and has since spread to several Indian states covering more than a million ha. Genetic studies and resistance characterization from multiple locations indicate independent evolution of resistance due to continuous use of isoproturon and monoculture rice–wheat-cropping system. Isoproturon-resistant biotypes were found cross-resistant to diclofop, but not to chlortoluron, which has the same mode of action as isoproturon. The isoproturon-resistance mechanism is metabolic degradation, mediated by P-450 monooxygenase enzymes. This type of resistance could become serious and lead to the evolution of multiple resistances to herbicides of different modes of action. Adoption of fenoxaprop-P, clodinafop, and sulfosulfuron in isoproturon-resistant areas since 1997 initially led to high yields, but resulted in a weed flora shift which eventually reduced yields and increased the cost of weed management. Although isoproturon recommendation has been withdrawn from rice–wheat cropping zones, resistance in littleseed canarygrass is spreading in other areas where isoproturon has been used for several years because it is inexpensive and has broad-spectum weed control. Management factors, such zero or minimum tillage, early planting after rice harvest, and alternative herbicides provide effective control of resistant biotypes. However, lower efficacy of these herbicides has been observed in the field, although multiple resistances have yet to be confirmed. Herbicide rotations, mixtures, and sequences are beneficial, but only in the short term. Improved cultivation practices are also helpful; however, no current single system is sustainable. An integration of tillage method, planting time, varietal selection, crop rotation, timing and method of herbicide application, optimum dose, and sanitation practices is crucial in managing herbicide-resistant littleseed canarygrass.