Monepantel (trade name Zolvix) is a new oral anthelmintic drug from a group of amino-acetonitrile derivatives with broad-spectrum activity against gastrointestinal nematodes of sheep, including adults and L4 larvae of the most important species. Monepantel have a novel mode of action involving a unique, nematode-specific clade of nicotinic acetylcholine receptor (nAChR) subunit ACR-23. Monepantel acts as a positive allosteric modulator of this receptor subunit, which is forced to open on stimulus but cannot close again, resulting in a constant uncontrolled flux of ions and finally in a depolarization of muscle cells leading to paralysis, spasmodic contractions of the anterior portion of the pharynx and ultimately death of adult nematodes. Monepantel-exposed C. elegans also exhibited molting defects and large vacuoles, characteristic for necrosis, are developed. Some nematode species lack ACR-23/MPTL-1 and predicted them to be Monepantel insensitive. Caenorhabditis nematodes equipped with ACR-23/MPTL-1 receptor subunits were found susceptible to Monepantel, whereas Pristionchus pacificus, closely related to these worms but lacking an ACR-23/MPTL-1 homolog, was tolerant. Monepantel shows an excellent tolerability in mammals and it is also active against multidrug-resistant parasites, indicating that its molecular target is absent or inaccessible in the host and is different from those of the classic anthelmintics. Safety pharmacological studies in rats indicate that MOP does not exert negative effects at a dose of 2000 mg/kg. Unfortunately, recent studies from New Zealand and Australia have reported that the efficacy of this new anthelmintic has declined markedly. Lack of efficacy of MOP was confirmed in the slaughtered sheep in which burdens of T. circumcincta and T. colubriformis showed no significant reductions. Whilst these two parasites now appear solidly resistant, the status of O. venulosum remains less clear.