St. John's Wort (Hypericum perforatum) is a member of the Hypericaceae family. The genus Hypericum contains around 400 species divided in 30 subgroups that are spread throughout temperate and tropical areas worldwide. More than 70 species have been investigated from a phytochemical viewpoint. H. perforatum is one of the most widely distributed species along with H. crispum and H. hirsutum. This plant, as other members of the Hypericaceae, is a prolific producer of secondary metabolites [I] and has been the topic of numerous phytochemical investigations due its ancient use as a vulnerary and especially, more recently, its widespread application as an antidepressant phytopreparation. Today, the registered phytomedicines consist of an alcoholic extract of the dried flowering tops of the plant. At least height natural product chemical classes are present in this plant; they include naphthodianthrones, phloroglucinols, flavonoids, biflavonoids, xanthones, proanthocyanidins, acid phenols as well as essential oils. Several review have already dealt with the constituents [2-4]. In spite of all the chemical studies performed on this widespread medicinal plant the major limitation to a rational exploitation of this plant is our still-limited knowledge on its active constituents. In this Chapter, a review of the current knowledge of the chemical composition of St. John's Wort is given.