Introduction: St. John's wort (SJW) is a common medicinal herb used for the treatment of mild to moderate depression. Hyperforin, one of the chief components of SJW, plays an important role in the induction of cytochrome P450 enzymes (CYP) and P-glycoprotein transporter (P-gp), and therefore, affects the pharmacokinetics of various drugs. There are several clinical studies demonstrating the interaction of SJW with the metabolism of conventional drugs which may cause life-threatening events. Areas covered: This review focuses on human studies that have evaluated pharmacokinetic alterations of conventional drugs in concomitant use with different SJW preparations. Expert opinion: SJW preparations have demonstrated clinically important interactions with several classes of conventional drugs such as immunosuppressants, anticancer agents, cardiovascular drugs, oral contraceptives, and lipid lowering agents that caused life-threatening events in several cases. The patient information label on the SJW products should provide enough information regarding the possible risk of interaction. Hyperforin seems to be the major ingredient responsible for CYP and P-gp inducing activity of SJW; thus, hyperforin-free products may be future candidates to decrease SJW's drug interactions.