Many cancers arise in epithelial mucosa. These mucosal surfaces are characterized by the induction of divergent immune responses, as they are both the main portal of entry for pathogens and a large niche of commensal bacteria and tolerized antigens. In addition, mucosa located in different anatomical sites harbor distinct typical features. Exploiting the different requirements for inducing an effective immune response at mucosal sites might help to define new immunotherapeutic approaches against epithelial cancers, at least in the case of differentiated tumors that have retained their mucosal characteristics.