Alterations in the immune system occur in advanced aging, which ultimately results in a failure to elicit pathogen-specific immunity in order to protect the host from infectious diseases. Since pathogen-specific mucosal immune response is the major player for host defense at mucosal surfaces, where various pathogens exist, it is important to understand age-associated changes in the mucosal immune system (mucosal immunosenescence) in order to develop effective mucosal vaccine for the elderly. Mucosal immunosenescence occurs initially in the gastrointestinal tract. Thus the diminished size of Peyer’s patches and reduced numbers of naïve CD4+ T cells, follicular dendritic cells (DCs), and antigen (Ag) uptake or microfold cells were noted during the aging process. On the other hand, the immunological functions of nasopharyngeal-associated lymphoid tissues remain intact during aging with notable signs of immunosenescence seen only in the elderly. To establish a healthy aging society, it is essential to develop immunologic strategies such as novel vaccines and immune therapies to combat pathogens. It has been shown that stem cell transfer as well as several mucosal adjuvant and delivery systems for activation of and deposition of Ag to mucosal DCs, respectively, are attractive and effective immunologic intervention approaches.