Macrocyclic lactones (MLs) have many anti-parasitic applications in small companion animal medicine. They were first developed as chemoprophylactics against heartworm (Dirofilaria immitis) infection to be applied monthly for retroactive killing of third- and fourth-stage larvae. ML-containing products formulated for oral (ivermectin, milbemycin oxime), topical (selamectin, moxidectin) or injectable sustained release (moxidectin, ivermectin) are approved for heartworm prevention in dogs or cats. Clearance of microfilariae and gradual or "soft" killing of adult heartworms constitute increasingly prevalent extra-label uses of MLs against D. immitis. Some commercial ML formulations contain sufficient levels of active ingredient (milbemycin oxime, selamectin, moxidectin) to support additional label claims against gastrointestinal nematode parasites such as hookworms (Ancylostoma spp.) and ascarid round worms (Toxocara spp. and Toxascaris leonina). Beyond these approved applications, safe, extra-label uses of MLs against nematodes parasitizing the urinary tract, such as Capillaria spp., and parasites of the tissues, such as Dipetalonema reconditum, Dirofilaria repens, Thelazia spp. and Spirocerca lupi, in dogs and cats as well as exotic pets have been reported. MLs as a group have intrinsic insecticidal and acaricidal activity, and topical or otic formulations of certain compounds (selamectin, moxidectin, milbemycin oxime or ivermectin) are approved for treatment and control of fleas, certain ixodid ticks, sarcoptiform and demodectic mange mites and psoroptiform ear mites. Extra-label applications of MLs against ectoparasites include notoedric mange mites, dermanyssids such as Ornythonussus bacoti, numerous species of fur mite (e.g. Cheyletiella spp. and Lynxacarus) and trombiculids ("chiggers") in cats, dogs and nontraditional or exotic pets.