Eosinophils have been shown to be potent effector cells for the killing of helminth parasites in in vitro cultures. However, an in vivo role for eosinophils has been more difficult to establish. Early data showed close associations between eosinophils and damaged or dead parasites in histological sections, and significant correlations between resistance to parasites and the capacity to induce eosinophilia after infection. However, more recent studies, using mice that have reduced or increased eosinophil levels through targeting of the eosinophil-specific cytokine interleukin 5, have not unanimously supported an in vivo role for eosinophils in resistance to parasites. Here, Els Meeusen and Adam Balic review these studies and suggest a major role for the innate immune response in unnatural mouse-parasite models to explain some of the findings. They conclude that the data so far are consistent with a role for eosinophils in the killing of infective larval stages, but not adults, of most helminth parasites.