The mouth is a vital route of drug administration with over 84 % of all medicines reportedly administered through it. The gastrointestinal system is equally imbued with a lot of adaptive features that make the oral route even more conducive for systemic drug delivery. The usefulness of the oral route is, however challenged by the existence of numerous absorption barriers which limit the effective absorption and delivery of drugs to their target sites in the body systems. Understanding these adaptive attributes, systemic barriers and available strategies for overcoming such barriers will not only be helpful in drug development and design but also useful to the formulation scientists desirous of optimizing drug delivery. The objective of this work was to review the gastrointestinal route of drug administration with respect to some biochemical and physio-anatomic features that impede or enhance drug absorption and to highlight current strategies that have been deployed to achieve optimum per oral drug delivery. The current review reveals the emerging roles of nanocarriers in oral drug delivery. Polymeric nanocarriers enhance the solubility, targeting and safety profiles of many important pharmacological agents. Novel systems that offer protection against gastro enzymes and as such, promote oral administration of biologicals are being widely investigated. Mechanical, magnetic, and acoustic energy – induced membrane perturbation are other delivery options receiving research attentions. It may be concluded that, with the avalanche of research efforts in the area, the oral route will maintain its prominence among other routes of drug administration.