Most therapeutic agents are delivered orally. Consequently, the major classes of therapeutically useful chemicals are partially lipophilic, small molecular weight compounds. They have reasonable permeability coefficient values across cell membranes, including those of intestinal epithelia and vascular endothelia. In contrast, large molecular weight biotechnology compounds have limited usefulness by non-injected routes as a consequence of their low membrane permeability and variable solubility. However, a wide range of infectious agents have developed strategies or have hijacked physiological routings in order to enter the host by the oral route. Efforts to address such issues have refreshed interest in mechanisms by which different types of payloads (including particulates and microorganisms) translocate across gut epithelia and then distribute to target tissues. Special attention is given to the potential role of the enteric nervous system and its plasticity.