Infections with gastrointestinal nematodes represent a major problem for human health and animal health and production. The physical size of the parasite, its changing life-cycle stages and the relative inaccessibility to host cells pose unique challenges to the immune system, which has evolved specialized strategies for parasite control. This paper reviews the work performed in the authors' laboratories to identify components that are involved in the natural rejection response against ruminant gastrointestinal nematode parasites, in particular Haemonchus contortus in sheep. The results of these studies indicate that stage-specific antibodies act in concert with effector cells, in particular globular leukocytes (intraepithelial mast cells) and eosinophils, appropriately activated/primed by type 2 (T2) cytokines, to initiate different mechanisms of parasite expulsion and killing. In addition, other molecules, in particular carbohydrate binding galectins, may be involved in strengthening the final effector phase of the rejection response.