To date, effectively controlling resistant weeds has been a great challenge in modern agricultural production. Developing new modes of action of herbicides would be an efficient, convenient, and timely means of controlling resistant weeds. In particular, new modes of herbicide action do not appear to have evolutionary resistance or cross-resistance with existing herbicides. However, a few successful herbicides with new modes of action (MoAs) have been marketed in the past 20 years. In this paper, we analyzed limiting factors for the slow development of novel herbicide MoAs. We then summarized the positive herbicide targets for the herbicides that have been discovered in recent years, such as Solanyl Diphosphate Synthase (SPS), Fatty Acid Thioesterase (FAT), Plastid Peptide Deformylase (PDEF), and Dihydroxy-Acid Dehydratase (DHAD). Some commercial herbicide varieties have been obtained based on novel herbicide targets, such as Homogentisate Solanesyltransferase (HST) and Dihydroorotate Dehydrogenase (DHODH). This provides a new reference and idea for herbicide molecular design in the future. In addition, some practical and efficient methods were mentioned for the rational design, discovery, and development of targeted herbicides development. In order to overcome the adverse conditions of compound druggability, prodrug strategies are also used in herbicide development, which can optimize the administration, permeability, absorption, and distribution of the original drug molecule or a candidate compound and may provide more possibilities for the development of new herbicides. The development of new herbicides is fascinating, the challenges and rewards are great, and the path to success is becoming more apparent.
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