Anthelmintic drugs constitute the primary means for treating and controlling infections with parasitic nematodes both in human and animals. However, ever-increasing levels of anthelmintic resistance are reported in all drug classes, involving virtually all of the most economically important parasites of domestic animals. Anthelmintic resistance is also becoming a significant concern in human medicine, especially with benzimidazole drugs, which are essential components of current therapeutic strategies. To establish sustainable control programs, it is essential to deepen our understanding of the mechanisms driving anthelmintic resistance in parasitic nematodes and, develop drugs with novel modes of action to overcome existing resistance. In chapters 2 and 3, we provide proof of concept and further validation of phosphoethanolamine methyltransferases (PMTs) as novel drug targets in parasitic nematodes. We first conducted the in vitro screening of a panel of 15 compounds with inhibitory activity against PMTs in Haemonchus contortus. Three PMT inhibitor compounds that showed in vitro activity in the lower micromolar range were then tested in vivo using the jird (Meriones unguiculatus) – H. contortus model. When tested in vivo, these compounds achieved relatively high reductions in worm counts, with efficacy ranging from 53.5% to 72.6%. The third study investigated development of benzimidazole resistance in a field population of H. contortus, focusing on genotypic changes and their correlation with drug-susceptibility. We applied a drug selection protocol involving 20 goats, and monitored drug-susceptibility through egg hatch and larval development assays. The results from these tests were correlated with the deep amplicon sequencing and haplotype analysis of beta-tubulin. GLOWORM-FL simulations were performed to predict levels of egg excretion and larval contamination of pastures. Additionally, the archived samples collected throughout our drug-selection field study, will serve as the basis for further studies investigating non-beta tubulin genomic loci under selection from benzimidazole drugs. Overall, this dissertation provides valuable insights into the dynamics of benzimidazole selection under field conditions, and strong evidence supporting the potential of a new drug target in parasitic nematodes. Compounds exhibiting activity against this novel target could serve as a new generation of broad-spectrum anthelmintic drugs for the treatment of nematode infections in animals and humans.