Naturally occurring macrocyclic peptides offer great potential as leads for drug design [1-3]. Our work focuses on a class of macrocyclic peptides known as cyclotides that are exceptionally stable and are resistant to enzymatic or thermal degradation by virtue of their cyclic cystine knot structural motif. They are excellent scaffolds for the incorporation of bioactive peptide epitopes to stabilise them. More than two dozen examples have now been reported where biologically active epitopes have been grafted onto cyclic peptide frameworks to produce drug lead molecules with potential in the treatment of cancer, cardiovascular disease, infectious disease, autoimmune disease (multiple sclerosis) and pain. This presentation will describe our work on the discovery, structural characterisation, biosynthesis [4] and applications of cyclotides, including studies of their cell permeability and applications to target intracellular protein:protein interactions.