Infections with gastrointestinal nematode parasites are a major problem for the sheep industry in Australia and New Zealand and have been the subject of intensive research to define mechanisms of resistance. The ability to take continuous biopsy samples of infected organs and cannulate both afferent and efferent lymphatics of draining lymph nodes has been particularly useful in illuminating the kinetics of immune responses at the site of infection. Distinct localized immune responses were shown to occur within and between sheep breeds at different sensitization regimes, as well as at different developmental stages of the parasite within the host. Using localized antibodies derived from mucus and lymph nodes, two major antigens have been identified on the infective L3 stage, which may be responsible for inducing protection and have potential as vaccine targets. Recent advances in sheep genomics also offer the potential of gaining further insight into the underlying genetics of resistance to nematode infections.