Amitraz is presently the only FDA-approved treatment for demodicosis in dogs in the United States. Amitraz treatment involves a protracted course of administration and risks of severe adverse effects such as sedation, bradycardia, and respiratory depression, which are caused by activation of α2-adrenergic receptors. Other treatment options include macrocyclic lactones and lime sulfur, but these products have varied efficacy and high risks of adverse effects. Several recent studies have indicated that isoxazolines are capable of reducing Demodex mite counts in canine and feline patients with demodicosis by ≥ 99% in as little as 1 month with few adverse effects. This article reviews the status of isoxazolines in regard to labeled uses in dogs and cats in the United States, extralabel clinical use for treatment of demodicosis in these species, and safety of orally administered formulations of these drugs.