Most viral infections occur via mucosal surfaces like the respiratory, gastrointestinal, or genital epithelium. The mucosal immune system is an important component of the body's defense against such infections and consequently induction of mucosal, in addition to systemic immunity, might improve vaccine efficacy. Several orally administered vaccines, for example, against poliovirus and gastrointestinal bacterial infections, have been developed and are widely used. In contrast, to date most vaccines against respiratory pathogens are applied parenterally and thus do not induce significant mucosal immunity. For the development of effective mucosal vaccines a more profound understanding of the immune mechanisms operative at mucosal surfaces and of the interplay between different mucosal compartments is needed. Moreover, factors like the dose, form of application, and type of mucosal adjuvants are critical to the induction of effective mucosal immunity. This brief review will focus mainly on the nasal route and will summarize some recent findings concerning the function of the mucosal immune system of the upper respiratory tract. Furthermore, routes of cross-immunization between distinct mucosal compartments and how they might be relevant to vaccine development will be addressed. Finally, I will outline critical factors for the rational design of nasal vaccines and in this context highlight some recent preclinical and clinical developments in the field.