Currently, only a few licensed vaccines against intestinal infections are available. Existing vaccines have shown good efficacy when used by travelers in industrialized countries. However, these vaccines have lower efficacy in endemic areas with high prevalence of enteric pathogens. Current vaccines are too expensive to be efficiently distributed in endemic countries. Immune correlates of protection are not well defined for current licensed vaccines. A better understanding of protection mechanisms at the intestinal mucosal surfaces should allow the development of more efficient vaccines. Gut physiology and microbial composition play an important role in both physical integrity and immunological status of the gastro-intestinal tract. These parameters can partially explain the disparities observed in current vaccines efficiency. Several next-generation vaccines combined or not with adjuvant able to promote a strong mucosal response in the intestine, are under preclinical and clinical investigations.