ABSTRACT: Till recently, injection remains the most common means of administering therapeutic proteins and peptides because of their poor oral bioavailability. Currently, there is a high level of interest in the use of the oral route as a portal for protein drug entry to the systemic circulation. As a site for drug delivery, the oral route offers advantages over the conventional parenteral and other alternative routes of drug administration. It provides high patient compliance, ease of administration, less expensive and ability to terminate delivery when required. The oral route appears to be a potential site for drug delivery to the systemic circulation. However, this site is associated with limitations that restrict its use as a route for the systemic delivery of drugs. The low permeability of the membranes that line the oral route results in a low flux of the drugs. Designing and formulating a polypeptide drug delivery through the gastrointestinal tract has been a persistent challenge because of their unfavourable physicochemical properties, which includes enzymatic breakdown, poor membrane permeability and large molecular size. Various strategies are currently under investigation which enhances drug penetration to improve bioavailability from less than 1% to at least 30-50%. These strategies involve chemical modification of the protein drugs, protease inhibitors, absorption enhancers, formulation vehicles and mucoadhesive polymeric systems. These pharmaceutical approaches which overcome various physiological barriers, help to improve oral bioavailability and ultimately achieve formulation goals for oral protein drug delivery.