Gene-encoded cyclic peptides were originally thought to be anomalies in the peptide world, but are now known to be widespread throughout nature, with examples in plants, bacteria, fungi, and mammals. The evolution is not well understood but recent studies have provided fascinating insights into how these cyclic peptides are made. The intrinsic stability associated with the cyclic backbone has piqued the interest of researchers and has led to the hypothesis that these cyclic peptides can be used as scaffolds in drug design. Gene-encoded cyclic peptides from plants have been of particular interest for drug design. The potential of plant-derived disulfide-rich cyclic peptides in the design of novel drug leads for a range of therapeutic applications, including cancer, will be discussed.