St. John's Wort (SJW, Hypericum perforatum) is effective in mild-to-moderate depression. As a monotherapy, SJW has an encouraging safety profile. However, numerous reports indicate the possibility of important interactions with prescribed drugs. SJW has been shown to lower the plasma concentration (and/or the pharmacological effect) of a number of drugs including alprazolam, amitriptyline, cyclosporine, digoxin, fexofenadine, indinavir, irinotecan, methadone, nevirapine, simvastatin, tacrolimus, theophylline, warfarin, phenprocoumon and oral contraceptives. Induction of P-glycoprotein and/or cytochrome P450 (CYP) enzymes (particularly CYP 3A4) by SJW could explain such pharmacokinetic interactions. When combined with serotonin reuptake inhibitor, antidepressants (e.g. sertaline, paroxetine, nefazodone) or buspirone, SJW can cause serotonergic syndrome. SJW represents a herbal medicine with a high potential for drug interactions. Some of such interactions may have serious clinical consequences.