A large proportion of pathogens either invade through, or cause disease at mucosal surfaces. Many new generation mucosal vaccine candidates lack important immunostimulatory features of the original pathogens and thus often do not elicit sufficiently strong immune responses. Despite numerous efforts, there is a profound lack of available agents with mucosal immunomodulatory and adjuvant activity. Immunomodulatory adjuvants are often derived from pathogens and thus efficiently activate the innate immune system leading to subsequent development of strong, specific acquired immunity. In this review, recent advances in mucosal immunomodulators/adjuvants are described with special emphasis on recently developed detoxified cholera toxin and Escherichia coli heat labile enterotoxin derivatives, and the newly described Toll-like receptor ligands CpG DNA and imidazoquinoline compounds. These agents hold much promise as useful mucosal immunomodulators/adjuvants for induction of strong innate immune response and also for subsequent development of specific acquired immunity against mucosal pathogens.