DiscussionCyclotides, or knottins, are plant-derived cystine knot microproteins. Despite their very high structural rigidity there is great sequence diversity within this family. This has allowed us to substantially modify the wild type primary sequence, generating diverse loop replacement libraries. We have used to phage display to select library members which demonstrate a range of modalities, including oral availability, traditional protein target-specific binding and the possibility of blood-brain barrier delivery of therapeutic peptides. Given their small size, in vivo stability, protease resistance and modular nature, these peptides offer exceptional potential as biotherapeutics and delivery agents. Specific examples will be discussed.