Physiological processes are regulated to a large extent by physical and chemical interactions between polypeptides. Although many small molecules have been discovered that can modulate such interactions and may be useful as drugs, the design of these agents purely from the knowledge of the details of a given protein-protein interaction, or through screening, remains difficult. Therefore, the peptidomimetic process, which aims at using peptides derived from either polypeptide binding partner directly, or after modification to improve affinity and physicochemical properties, continues to be attractive. The vast majority of naturally occurring polypeptides are composed of L-amino acids. Because natural proteins need to be metabolised, L-amino acid polypeptides are very prone to proteolytic degradation, a property that severely limits their therapeutic application. The proteolytic machinery is not well equipped to deal with D-amino acid polypeptides, however, and it is this finding above all else that has spurned research into stereochemical and directional manipulation of peptide chains. The expectation has been that systematic inversion of the stereochemistry at the peptide backbone α-carbon atoms, if accompanied by chain reversal, should yield proteolytically stable retro-inverso peptide isomers, whose side chain topology, in the extended conformation, corresponds closely to that of a native sequence, and whose biological activity emulates that of a parent polypeptide. The actual structural implications of modifying amino acid stereochemistry and peptide bond direction are reviewed critically here and the reasons for the lack of general success with this strategy are discussed. The application of polypeptides is particularly pertinent to synthetic vaccine design. Interestingly, the retro-inverso strategy has been more successful for immunological applications than elsewhere; recent finding are collated in this review. Partial rather than global retro-inversion holds much promise since the loss of crucial backbone hydrogen-bonding through peptide bond reversal can be avoided, while still permitting stabilisation of selected hydrolysis-prone peptide bonds. Generically applicable synthetic methods for such partially modified retro-inverso peptides are not as yet available; progress towards this goal is also summarised.