Cyclotides are plant-derived peptides with a cyclic backbone and knotted topology of disulfide bonds. Their extreme stability and natural sequence variation has led to the suggestion that they might be useful as scaffolds to stabilize bioactive sequences. Recent studies have shown that anti-angiogenic activity and protease inhibitory activity against a foot and mouth disease protease can be grafted onto the cyclotide framework. There has also been significant progress made in determining the mechanism of cyclization of cyclotides and in producing cyclotides using bacterial expression and plant cell culture. There is a wide range of disease states that can be targeted using the cyclotide framework and the advances that have been made in the production of cyclotides will facilitate their development as pharmaceutical templates.