Oral route is the most common route for the delivery of drugs because it is simple to implement and improves patient compliance and quality of life. However, oral absorption is limited by various physiological barriers and remains a scientific challenge. Nanometric-sized drug delivery systems are being extensively studied and provide promising potential for oral drug delivery. Many different technological solutions have been proposed to enhance the bioavailability or the targeting of drug after oral administration. To reach these goals, it is important to analyze the biopharmaceutical parameters to consider in order to alter the fate of nanocarriers after oral delivery. In the present review, the gastrointestinal barrier and physiological stress factors with regard to nanocarriers' performance or integrity issues are first described. Second, the different characteristics offered by the nanocarriers (size, surface composition and properties mediated by external factors such as ligands) and their effect on the optimal transport of drug into the bloodstream are discussed. Finally, the integrity issue is discussed in function of the expected role of the nanocarriers: bioavailability enhancement or pharmacological targeting.