Abstract BACKGROUND: The herbicide sulfonylurea (SU) belongs to one of the most important class of herbicides worldwide. It is well known for its ecofriendly, extreme low toxicity towards mammals and ultralow dosage application. The original inventor, G Levitt, set out structure–activity relationship (SAR) guidelines for SU structural design to attain superhigh bioactivity. A new approach to SU molecular design has been developed. RESULTS: After the analysis of scores of SU products by X‐ray diffraction methodology and after greenhouse herbicidal screening of 900 novel SU structures synthesised in the authors' laboratory, it was found that several SU structures containing a monosubstituted pyrimidine moiety retain excellent herbicidal characteristics, which has led to partial revision of the Levitt guidelines. CONCLUSIONS: Among the novel SU molecules, monosulfuron and monosulfuron‐ester have been developed into two new herbicides that have been officially approved for field application and applied in millet and wheat fields in China. A systematic structural study of the new substrate–target complex and the relative mode of action in comparison with conventional SU has been carried out. A new mode of action has been postulated. Copyright © 2011 Society of Chemical Industry