Polypeptide binders can offer significant selectivity and potency, and hence are excellent candidates for the treatment of various diseases and human disorders. One major bottleneck is that many peptide candidates suffer from proteolytic degradation, both limiting the option of the delivery methods and eliciting unwanted immune responses caused by major histocompatibility complex (MHC) presentation by immune cells. Peptides comprised of Damino acids are a viable approach as they are non-recognizable by endogenous proteases. It has been suggested that Dpeptide binders can be made by retro-inversion (RI) which relies on flipping the entire peptide chain from the N-to C-termini to offset the flip in the side chain chirality. Though some success has been seen in short binders, it was quickly discovered that this double-flip approach did not reinstate the true peptide structure and, in some cases, could drastically weaken the peptide binding. Recently, binders composed of both D-and L-residues have been developed through ribosomal engineering. In order to create binders entirely composed of D-amino acids, the most routine approach is mirror-image phage display (MIPD). In MIPD, D-enantiomers of protein targets are synthesized and subjected to L-peptide screening (Figure ). Due to the nature of mirror-image symmetry, the same-sequence D-peptide will bind to the native L-protein target with equal affinity, thus yielding an inherently non-proteolytic peptide binder. MIPD has discovered Dpeptide binders for a range of targets (Table ). Key examples are summarized below: