Weed resistance to herbicides has increased exponentially during the past 30 to 40 years, consequently reducing the number of effective products available to control certain species and populations. Future efforts should target not only the discovery of new protein binding sites and the development of new molecules, but also the revival of old molecules with reduced efficacy due to widespread herbicide resistance. The addition of herbicide synergists that inhibit metabolic pathways or enhance intrinsic plant stress is a possible solution to ameliorate the negative effects caused by the lack of new herbicide chemistries. Glutathione S-transferase (GST) enzymes are involved with numerous herbicide detoxification reactions and plant stress responses. This review approaches the potential use of natural and synthetic GST-inhibitors to enhance herbicidal activity or induce crop safety to provide effective, sustainable weed management strategies in the future.