Nematodes parasitize an alarming number of people and agricultural animals globally and cause debilitating morbidity and mortality. Anthelmintics have been the primary tools used to control parasitic nematodes for the past several decades, but drug resistance is becoming a major obstacle. Xenobiotic detoxification pathways defend against drugs and other foreign chemicals in diverse organisms, and evidence is accumulating that they play a role in mediating resistance to anthelmintics in nematodes. Related antioxidation pathways may also provide filarial parasites with protection against host free-radical-mediated immune responses. Upstream regulatory pathways have received almost no attention in nematode parasites, despite their potential to coregulate multiple detoxification and antioxidation genes. The nuclear eurythroid 2-related factor 2 (NRF2) transcription factor mediates inducible detoxification and antioxidation defenses in mammals, and recent studies have demonstrated that it promotes multidrug resistance in some human tumors. Recent studies in the free-living model nematode, Caenorhabditis elegans, have defined the homologous transcription factor, SKN-1, as a master regulator of detoxification and antioxidation genes. Despite similar functions, SKN-1 and NRF2 have important differences in structure and regulatory pathways. Protein alignment and phylogenetic analyses indicate that these differences are shared among many nematodes, making SKN-1 a candidate for specifically targeting nematode detoxification and antioxidation.