Conventional forms of administrations of nonabsorbable drugs and peptides rely on their parenteral injection. The intestinal epithelium represents the major barrier to the oral absorption of these therapeutical agents into the systemic circulation. Recently, a number of innovative drug delivery approaches have been developed, including the drug entrapment within small vesicles or their passage through the intestinal paracellular pathway. Zonula occludens toxin, a recently discovered protein elaborated by Vibrio cholerae, provided tools for gaining more insights on the pathophysiology of the regulation of intestinal permeability and to developing alternative approaches for the oral delivery of drugs and macromolecules normally not absorbed through the intestine.