This review discusses drawbacks to peptide and protein oral formulations related to these drugs' chemical and physical instability. Means used to overcome such limitations are mentioned and discussed in parallel with manufacturing considerations, metabolism, absorption mechanisms and the efflux systems that peptides and proteins experience as they travel through the gastrointestinal tract. Special focus is given to the use of delivery systems based on nanoparticles and cyclodextrins. Advantages of these systems relate to the protection from degradation, enhancement of absorption, targeting and controlling the release of the drug. Biodistribution and safety issues are discussed once material from the delivery system is expected to be absorbed by the body and thus interact with biological components. Operating parameters regarding nanoparticle manufacture and composition are also overviewed since nanoparticle physicochemical characteristics influence the ability to successfully entrap the intended drug as well as interaction with body.