Ivermectin is a drug of incredible public health importance that’s used in mass drug administration programs to eliminate lymphatic filariasis and onchocerciasis. The recent WHO recommendation of triple drug therapy for lymphatic filariasis MDA and the adoption of the 2021-2030 Road Map for Neglected Tropical Diseases likely mean use of ivermectin in elimination programs for lymphatic filariasis will expand worldwide. In lymphatic filariasis, caused by Wuchereria bancrofti, Brugia malayi, and B. timori, ivermectin causes long lasting suppression of the production of the transmittable blood-stage form called microfilariae (Mf) and rapidly clears Mf from the bloodstream. Despite ivermectin’s decades long global use, we still don’t have a full understanding of how it clears filarial parasites, and the recent expansion and challenges of ivermectin use make this understanding even more critical. Ivermectin’s potency in vivo, but not in vitro, suggests that a host component may be involved, likely the immune system. To examine this, parasite naïve patients were given the label dose of ivermectin used in mass drug administration campaigns, and we compared their immune functioning to a placebo treated group. We found that there was no difference between the groups in their complete blood counts, cytokine levels, expression of a panel of innate immunity genes, or the ability of their immune cells the kill microfilariae. We previously performed a transcriptomics study in which gerbils infected with B. malayi were treated with ivermectin and differently expressed candidate genes were then investigated in phenotypic assays of ivermectin response using mutant strains of C. elegans. Through this approach we have identified several genes that influence resistance and hypersensitivity to ivermectin and found that the processes of development and fertility are affected by ivermectin independently of each other. This research has contributed to our understanding of ivermectin’s mechanism of action against filarial worms, including a lack of evidence for the involvement of host immunity and a selection of new candidate genes and pathways involved in ivermectin resistance and hypersensitivity.