Adaptive humoral immunity mediated by secretory antibodies appears to be desirable in the defence against mucosal virus infections. Specific secretory immunoglobulin A (SIgA) can inhibit initial pathogen colonization by performing immune exclusion both on the mucosal surface and within infected secretory epithelial cells without causing tissue damage. Like natural infections, live topical vaccines or adequate combinations of inactivated vaccines and mucosal adjuvants give rise not only to SIgA antibodies, but also to longstanding serum IgG and IgA responses. The intranasal route of vaccine application appears particularly attractive to achieve this result. The degree of protection after vaccination may range from complete inhibition of re-infection to reduction of symptoms. In this scenario it is generally difficult to determine unequivocally the relative importance of SIgA versus serum antibodies. However, infection models in knockout mice support the notion that SIgA exerts a decisive role in protection and cross-protection against influenza.