Introduction: Cyclotides are bioactive mini-proteins from plants that have the unique topological feature of a head-to-tail cyclic backbone combined with a cystine knot. Because of this structure they are ultra-stable and have attracted interest as peptide-based templates for drug design applications. Cyclotide biosynthesis involves processing from a genetically encoded precursor protein but methods have been developed for their man-made synthesis using solid phase peptide synthesis as well as recombinant methods. Their natural function in plants is as insecticidal agents and thus they have potential applications in agriculture. However, they have a range of pharmaceutically relevant activities, including anti-HIV, antimicrobial and uterotonic activity. Their exceptional stability and facile synthesis lend them to uses as pharmaceutical templates into which bioactive peptide sequences can be grafted. Areas covered: This article reviews the patent literature associated with cyclotides with a focus on therapeutic applications. These patents are primarily related to the use of cystine knot scaffolds for the production of peptide-based drug leads, molecular probes or diagnostic agents. Expert opinion: Although no cyclotide-related peptide has yet reached clinical trials, proof-of-concept has been obtained that bioactive peptide sequences can be grafted onto a cyclotide framework, maintaining biological activity while becoming resistant to proteolysis. Thus, cyclotides are promising templates in drug development applications and there is increasing interest in them and related cystine knot scaffolds, as well as in the use of other disulfide-rich scaffolds, in drug design.