The authors review the ultra-structural aspects and permeability features of normal human oral mucosa, after having recently tested and used it as a new site of systemic drug delivery. The pertinent scientific literature from 1975 through 2009 has been analysed and discussed. Buccal epithelium is a relatively permeable, robust non-keratinized tissue and blood vessels drain directly into the jugular vein; due to its particular features, it has been of increasing interest to researchers as an alternative site of drug administration. The review describes the structure and function of the buccal mucosa, the rationale for transbuccal drug delivery and the main transmucosal drug delivery systems. Recent studies have investigated the delivery of a variety of drugs through the buccal mucosa in order to assess both local and systemic, either positive or adverse, effects. In conclusion, buccal mucosa may be considered a promising site for effective, safe and non-invasive transmucosal sustained drug delivery.