Foot-and-mouth disease virus (FMDV) causes a highly infectious and economically devastating disease of livestock. The FMDV genome is translated as a single polypeptide precursor that is cleaved into functional proteins predominantly by the highly conserved viral 3C protease, making this enzyme an attractive target for antiviral drugs. This talk will describe attempts to develop inhibitors of this enzyme by means of producing a variety of different peptide analogues, as well as efforts to identify non-peptidic inhibitors. Both the nature of the warhead that targets the catalytic cysteine and the sequence of the peptidic region, which allows specificity, have been varied. Compounds have been tested for efficacy against the enzyme and also against live virus. Although there is still some way to go, we have produced compounds with EC50 values in the sub-micromolar range against the virus, which represent the most potent inhibitors yet described for this virus.