Parasitic nematode infections impact human and animal health globally, especially in the developing world. Anthelmintic drugs are the major line of defense against these infections, but the arsenal is limited. Additionally, anthelmintic resistance is widespread in veterinary parasites and an emerging threat in human parasites. Discoveries of the mode of action of these drugs and mechanisms of resistance have predominantly come from studies of a related non-parasitic nematode species, Caenorhabditis elegans, and the parasitic nematode Haemonchus contortus. Here, we discuss recent progress understanding anthelmintic resistance using these two species and how that progress relates to laboratory and field-based studies of veterinary helminths. We present a powerful approach enabled by the strengths of both nematode species to understand mechanisms of resistance and modes of action of anthelmintic drugs.