Amaranthus tuberculatus is the major weed species in many midwestern US row-crop production fields, and it is among the most problematic weeds in the world in terms of its ability to evolve herbicide resistance. It has now evolved resistance to herbicides spanning seven unique sites of action, with populations and even individual plants often possessing resistance to several herbicides/herbicide groups. Historically, herbicide target-site changes accounted for most of the known resistance mechanisms in this weed; however, over the last few years, non-target-site mechanisms, particularly enhanced herbicide detoxification, have become extremely common in A. tuberculatus. Unravelling the genetics and molecular details of non-target-site resistance mechanisms, understanding the extent to which they confer cross resistance to other herbicides, and understanding how they evolve remain as critical research endeavors. Transcriptomic and genomics approaches are already facilitating such studies, the results of which hopefully will inform better resistance-mitigation strategies. The largely unprecedented level of herbicide resistance in A. tuberculatus is not only a fascinating example of evolution in action, but it is a serious and growing threat to the sustainability of midwestern US cropping systems. © 2020 Society of Chemical Industry. © 2020 Society of Chemical Industry.