The rapid emergence of weeds resistant to our current herbicides has prompted serious concerns over the sustainability and profitability of farming systems. Therefore, we urgently require herbicides with new modes of action to tackle the herbicide resistance crisis we are facing. Although many commercial herbicides inhibit the biosynthesis of amino acids in plants, the lysine biosynthesis pathway is yet to be exploited as a herbicide target. Our goal is therefore to identify inhibitors of lysine biosynthesis enzymes and validate them as novel herbicide leads. Additionally, we aim to circumvent the emergence of resistance by combining inhibitors into a ‘herbicide cocktail’. To achieve this, we have focused on the investigation of the structure-activity relationship of small molecule inhibitors of several lysine biosynthesis enzymes. Screening is being conducted in vitro against recombinant proteins, as well as in planta against pre and post emergent Arabidopsis thaliana plants. The relationship between lead inhibitor mechanisms and physiological outcomes is being probed using X-ray crystallography, toxicity assays, and systems biology. Lastly, we will ascertain if any synergistic effects may be afforded by combining these inhibitors and investigate potential resistance mechanisms.