In this review, we focus on six key areas currently receiving attention in the mucosal immune system. These six areas are of considerable importance for development of vaccines. They are (a) the necessity to understand the unique features of the mucosal immune system; (b) the possibility that the common mucosal immune system may contain distinct compartments; (c) differences in antigen uptake and in types of antigen-presenting cells in mucosal inductive and effector sites; (d) more careful consideration of mucosal memory in vaccine development; (e) recent studies, which show that oral vaccines induce T-helper (Th)-cell subsets that regulate mucosal IgA responses; and (f) the mechanisms whereby mucosal S-IgA and T cells provide mucosal immune protection. An example of the above suffices to illustrate why the selected areas are of importance in vaccine development. Oral immunization preferentially induces type 2 Th (Th2) cell responses that directly correlate with antigen-specific IgA responses in mucosal effector sites. It is likely that activated, antigen-specific Th2 cells that are induced in Peyer's patches are continuously supplied to mucosal effector sites for regulation of IgA responses. These Th2 cells are producing cytokines such as interleukin (IL)-5 and IL-6 and these cytokines may direct antigen-specific surface IgA-positive B cells to become IgA-producing plasma cells. Nevertheless, additional studies will be required to establish that IgA responses to T-cell-dependent antigens depend on Th2 cell-derived help. What are the implications of these studies for current oral vaccines, including novel antigen delivery systems? The most obvious would be that vaccines should be optimized for induction of Th2-cell responses in IgA inductive sites such as the gut-associated lymphoreticular tissues. It is now clear that induction of Th2-type responses in both mucosal inductive and mucosal effector sites are essential for oral vaccines to induce S-IgA responses. However, antigens delivered by live vectors such as Salmonella typhimurium in the murine system and S. typhi in humans must consider T-cell responses induced against a live vector in addition to the inserted recombinant antigen. In this regard, it has been shown that these microorganisms induce cell-mediated immunity responses that largely result from Th1-type cells.(ABSTRACT TRUNCATED AT 400 WORDS)