Oral immunization is sought as a practical way to reduce the devastating morbidity and mortality caused by enteric diseases in children under the age of five living in the developing world. Licensed oral vaccines against polio, rotavirus, cholera and typhoid fever have had a major impact reducing global disease burden and mortality. A quandary that remains to be solved is the diminished immunogenicity and efficacy of these vaccines when given to subjects living in underdeveloped areas of the world as compared to people living in industrialized nations. Low socioeconomic status, poor living conditions, malnutrition and natural barriers that affect people living in less privileged countries are major determinants of vaccine performance. Novel protective antigens, adjuvants and immunization approaches to overcome these barriers are being explored. Understanding the processes involved in the induction of mucosal and systemic immunity by orally delivered antigens, the influence of multiple competing elements and the delicate balance between immune activation and tolerance in the gut is essential to assist the development and evaluation of vaccine candidates. Modern technology (e.g. genomics, proteomics, high throughput immunological assays using non-invasive specimens and mathematical modeling to dissect correlates of protection) will be essential to this task. Ultimately, well conducted clinical trials in high and low income countries will be needed to determine safety and effectiveness of vaccine candidates that appear to be promising in animal models. This chapter reviews the basis for immunological priming by orally delivered antigens in the gastrointestinal tract and the ensuing effector responses in humans. It also provides a summary of oral vaccines available, factors that affect efficacy of oral vaccines in developing countries as well as the ongoing efforts to develop more effective vaccine candidates.