Abstract: Cyclotides are plant-derived ultrastable peptides that are stabilized by head-to-tail cyclization backbone and three disulfide bonds that form cystine knots. This unique topology allows them to be exceptionally stable against chemical, thermal and biodegradability compared to other similarly sized peptides. Their excellent stability and tolerance to sequence substitution enable them to be used as frameworks for drug design. This article mainly introduces the application of cyclotides in three areas of pharmaceutical research, especially the recent progress in grafting bioactive peptide sequences onto the framework of cyclotides to generate new biological activities.