The triple helix is an important motif found in the family of collagens as well as a set of host-defense proteins. This conformation may be identified by its strict sequence constraints, including glycine as every third residue and a high content of imino acids. The first high-resolution structure available for a triple helix has confirmed the model of three supercoiled polyproline II-like helices and has defined a highly ordered water network whose regularity depends on the presence of 4-hydroxyproline. The role of the rod-like triple helix lies in its capacity to self-associate in a variety of forms as well as its ability to bind a wide range of ligands. The extensive hydrogen-bonded water network, together with the high content of sterically restricted imino acids, are the major contributors to the stabilization of triple helices, whereas electrostatic and hydrophobic interactions define intermolecular association and ligand binding. Mutations in the repeating Gly-X-Y sequences of triple helices have been shown to cause a variety of human diseases.