ABSTRACT1‐Deoxy‐D‐xylulose‐5‐phosphate reductoisomerase (IspC) is a key enzyme in the MEP pathway, essential for many bacteria, human pathogens, and plants, thus being an attractive drug target. Fosmidomycin, a potent IspC inhibitor with hydroxamate metal‐binding pharmacophores (MBPs), has entered clinical trials for malaria but is hampered by pharmacokinetic and toxicity issues of the hydroxamate fragment. This has led to increased interest in non‐hydroxamate inhibitors. This review focuses on the crystal structure and active‐site binding mode of IspC, and the structural types, inhibitory activities, and structure–activity relationships of non‐hydroxamate IspC inhibitors. Early attempts to design such inhibitors involved direct removal or replacement of the hydroxamate MBPs, with varying results. Lipophilic inhibitors, bisubstrate inhibitors, and those developed for herbicidal applications have shown promise. However, challenges remain due to the sensitivity of the enzyme active site to ligand interactions. Future research could draw from other metalloenzyme studies to develop novel and efficient non‐hydroxamate IspC inhibitors.