Herbicide-resistant weeds, especially those with resistance to multiple herbicides, represent a growing worldwide threat to agriculture and food security. Natural selection for resistant genotypes may act on standing genetic variation, or on a genetic and physiological background that is fundamentally altered because of stress responses to sublethal herbicide exposure. Stress-induced changes include DNA mutations, epigenetic alterations, transcriptional remodeling, and protein modifications, all of which can lead to herbicide resistance and a wide range of pleiotropic effects. Resistance selected in this manner is termed systemic acquired herbicide resistance, and the associated pleiotropic effects are manifested as a suite of constitutive transcriptional and post-translational changes related to biotic and abiotic stress adaptation, representing the evolutionary signature of selection. This phenotype is being investigated in two multiple herbicide-resistant populations of the hexaploid, self-pollinating weedy monocot Avena fatua that display such changes as well as constitutive reductions in certain heat shock proteins and their transcripts, which are well known as global regulators of diverse stress adaptation pathways. Herbicide-resistant populations of most weedy plant species exhibit pleiotropic effects, and their association with resistance genes presents a fertile area of investigation. This review proposes that more detailed studies of resistant A. fatua and other species through the lens of plant evolution under stress will inform improved resistant weed prevention and management strategies. © 2018 Society of Chemical Industry.