The prevalence of resistance to broad-spectrum anthelmintics among veterinary helminths has dramatically increased and has evolved from a scientific curiosity into a serious crisis facing small ruminant production in many countries. It also poses a veritable threat to other livestock and human helmiths. Both the molecular mechanisms of action and mechanisms of resistance of anthelmintics are poorly understood. Benzimidazoles bind to nematode β-tubulin, preventing microtubule aggregation and leading to paralysis and death. Levamisole acts through nicotinic acetylcholine receptor of the parasite muscle, causing membrane depolarization and contraction resulting in paralysis. Macrocyclic lactones modulate L-glutamate-gated chloride channels present on the pharynx and somatic muscle membrane of the parasites, thereby paralyzing them. Modes of action of schistosomicides and fasciolicides remain incompletely defined. A number of helminths have developed multiple resistance making their control difficult or almost impossible. As chemotherapy remains the mainstay of helminth control, ways of preserving the efficacy of the anthelmintics must be sought. Complete grasp of the molecular events and the underlying Darwinian selection in the parasites is the ultimate challenge if the persistent dilemma is ever to be alleviated, and that goal is yet an unforeseeable vista.