Intranasal administration of laboratory passaged wild-type influenza viruses to adults induces a mild upper respiratory illness accompanied by nasopharyngeal shedding of virus. A second model has used inoculation of children with attenuated viruses as a surrogate for wild-type infection. Generally, results of studies of antiviral or vaccine approaches in the challenge model have been predictive of efficacy in the real world, but it is recognized that the model does not reproduce naturally acquired illness well and both viral shedding and symptoms in the challenge model are mostly restricted to the upper respiratory tract. Serum antibody plays a major role in protection in this model and it is difficult to infect adults who have serum HI titres of > 1:8. Among adults with lower levels of HI antibody, a variety of protective factors have been described, including nasal IgA and serum NI antibody, and CTL. In some challenge studies, subjects have been protected despite lack of a measurable immune response to vaccination. Because measurement of mucosal antibody has been difficult to standardize, there is not a level that can be considered a cut-off for susceptibility. Use of a consistent method for assessing mucosal IgA between studies may help to derive a target level for vaccination.