Resistance to the macrocyclic lactones (MLs) has been confirmed or suspected in many target organisms and is a serious problem in some. For some species, such as parasitic nematodes of small ruminants, ML resistance has become severe enough to threaten effective worm control worm control. Resistance is also a major concern in horse parasites and an emerging problem in cattle. Despite this, we have insufficient understanding of the mechanisms of ML resistance, especially in nematodes. Some insect and mite agricultural pests express higher levels of detoxifying enzymes, leading to cross-resistance to other pesticide classes. A major difficulty is in the identification of true resistance and distinguishing this from other causes of treatment or prophylaxis failure – some in vitro assays for ML resistance are available but more are badly needed. Changes in the way anthelmintic drugs are used in livestock farming have been proposed, based on the treatment of those animals that would benefit most, and schemes have been devised for identifying those animals, flocks and herds. The continued sustainable use of these invaluable drugs may depend on the adoption and improvement of such schemes, as resistance is likely to become an ever more serious problem.