We report here the synthesis of human endothelin-2, a peptide of 21 amino acid residues with two disulfide bonds, based on the novel idea of a disulfide-driven cyclic peptide synthesis (DdCPS). This synthesis has two steps: (1) a one-pot solid-phase disulfide ligation of two different sulfur-containing peptide fragments using an Npys-Cl resin and (2) intramolecular cyclization of the disulfide peptide via amide bond formation using a thioester ligation. Human endothelin-2 was obtained in a total yield of 2.2% with two such DdCPS procedures and subsequent deprotection and HPLC purification. This strategy is the basis of a new solid-phase assisted practical synthesis of cyclic disulfide peptides.