The example of St. John's wort offers convincing evidence for the concept that modern methods of pharmacological and phytochemical research are effective in advancing the development of traditional herbal remedies. As a consequence of these efforts, it is known today that several compounds from different structural groups and with different mechanisms of action seem to be responsible for the observed antidepressant efficacy of St. John's Wort. Co-effectors in the extract improve the bioavailability of active constituents such as hypericin (1) (pharmacokinetic synergy). Unwanted side effects are preventable without remarkable loss of activity when the responsible constituent(s) are carefully removed during the extraction process, as demonstrated for hyperforin (3), which is responsible for the induction of cytochrome P450 (CYP)-metabolizing enzymes (CYP3A4, in particular). On the basis of our findings, it is likely that positive interactions between single compounds occur more frequently in traditionally used herbal preparations than is known presently.