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Permeation enhancers have been formulated in oral peptide tablets and capsules for over 40 years, mostly associated with failure. Bioavailabilities of 1-2% in large animals and people were achieved with macromolecules (heparin, calcitonin, insulin), but such formulations did not progress because bioavailability values were too low and variable, and some payloads had a low therapeutic index. All changed with the approvals of MYCAPPSA and RYBELSUS for octreotide and semaglutide using medium chain fatty acids (caprate) and derivatives (SNAC) as enhancers. Bioavailabilities were actually no better than seen in past decades, but the difference for semaglutide in particular, was the advent of a long half life potent peptide. Much has been achieved in working out the mechanism of action of enhancers in the gut using advanced microscopy, biophysical techniques, and molecular simulations. Drug hunters are bringing macrocycles of ~2000 Da in Mw to clinical trials and some are inherently gut-stable and may only require 1-2% bioavailability, which may be achieved without enhancers in some cases. For this Discovery audience, the two speakers both with backgrounds in knowledge of enhancers and oral peptide programmes, will highlight GI physiology issues that impact the performance of peptides and enhancer oral dosage forms, considerations for assessing the potential risks and opportunities for permeation enhancer enabled exposure of peptide drugs, the problems in translating from animals to humans, and will give their perspectives on where this field is going.