In parallel, the chemistry landscape for stapled peptides is continuously diversifying with a dozen “novel” linker chemistries reported in publications in 2019. found 78 stapled peptides where structural information has been submitted to the protein databank (PDB), of which 55 also had binding affinity reported. Hence stapled peptides have predictably sparked a growing interest from the scientific community since the early 2000s and have emerged as a potential new class of drugs. Moreover, their metabolites are relatively safe, and recent studies suggest that stapled peptides offer an advantage over traditional drugs by averting the development of drug resistance. Stapled peptides, whereby cross-linking of two or more side-chains is carried out via chemical synthesis, generally have a more compact structure, enhanced cell penetration, and are more resistant to proteolysis. Thus, stabilisation of secondary structure, be it through the introduction of non-peptidic fragments, backbone modifications, or unnatural amino acids to the sequence has been a prominent feature of peptide drug development since the 1990s. Notably the first seven FDA-approved peptidic drugs (Insulin, Adrenocorticotropic hormone, Calcitonin, Oxytocin, Vasopressin, Octreotide and Leuprorelin) all had a stabilised, or constrained, secondary structure, which is linked to improved resistance to proteolysis. However, shorter peptides were also marketed during the same period including vasopressin, a natural 10-mer peptide hormone. Some of the earliest peptide drugs developed over 50 years ago, were natural hormones such as insulin, erythropoietin, oxytocin, secretin and calcitonin, which all have comparatively high molecular masses (3-7 kDa). Short peptides with natural aminoacids usually have poor drug-like properties since they frequently have high conformational variability, low cell penetration, and undergo rapid proteolysis while longer peptides can be challenging both to produce and deliver in cells. But with 140 peptides in clinical development in 2019, interest in this class of therapeutics is clearly growing and constrained peptide technologies have attracted attention from larger pharmaceutical companies as well as academic laboratories and smaller start-ups. As a consequence, between 20 only 13 synthetic peptide drugs reached the European market. Despite heavy investment in the early 21st century, a number of challenges have stalled the development of marketable peptide therapeutic drugs.