Agrochemical expenditure places a significant social and economic burden on farmers operating on tight margins. In-season chemical costs alone have been shown to be in the range of $46/ha and $42/ha for herbicide and fungicide applications in Western Australia, representing almost 50% of production costs. When considering yield losses and physical management costs, the impact of weeds are of great concern to Australia’s $71 billion agricultural sector. Consequently, the rise in herbicide resistance is of significant economic importance, with new protein targets, chemical classes and strategies needed to avert this rise. However, the stagnation of agrochemical discovery is evidenced by no herbicide with a new mode of action being available in Australia for over 30 years. This research characterises two new protein targets, HMG-CoA reductase and dihydrofolate reductase, for herbicide development. Through a comprehensive understanding of these proteins' structures, we exploited the differences between human and plant proteins to create herbicidal compounds with target specificity. Additionally, we conducted extensive screening of ultra-large chemical libraries to discover new chemical scaffolds and engineered tolerant strains, paving the way for subsequent advancements in agrochemical development.