Filariasis is a widespread tropical disease caused by a group of nematode parasites that can survive for many years in immunocompetent hosts. The paradox of filariasis has always been the inverse association between parasite density, in terms of circulating microfilariae in the blood, and severe pathology. In this review, Rick Maizels and Rachel Lawrence argue that microfilariae and adult parasites induce a form of immunological tolerance which prevents both parasite elimination and progression to disease. The breakdown of this unresponsiveness is seen as the critical step towards pathogenesis. However, not every exposed individual progresses through infection to disease. The authors discuss evidence for protective immunity acting on antigens from the mosquito-borne infective larva, and propose that this stage represents a vulnerable target outside the scope of tolerance and pathogenesis. Stage-specific larval antigens, to which asymptomatic hosts are known to respond, may therefore represent the most effective and safe choice for an anti filarial vaccine.