Oral delivery of macromolecular drugs, particularly peptides and proteins, is the focus of many academic and industrial laboratories. Armed with an increased understanding of the structure and regulation of intestinal epithelial junctional complexes of the paracellular barrier, the development of permeation enhancement technology initially focused on the specific and reversible opening of tight junctions in order to enable oral delivery. Despite intense research, none of these specific tight junction-opening technologies has yet been approved in an oral drug product, likely because of poor efficacy. Less specific enhancer technologies with a long history of safe use in man have additional surfactant-like effects on the transcellular pathway that lead to improved efficacy. These are likely to be the first to market for selected poorly permeable peptides. This review presents a summary of some approaches taken to intestinal permeation enhancement and explores in detail the oral delivery system developed by Merrion Pharmaceuticals, Gastrointestinal Permeation Enhancement Technology (GIPET).