In spite of modern medical advances, herbal dietary supplements continue to be widely used for health maintenance, disease prevention, and even disease treatment. The ADME mechanisms for the known herb–drug interactions involve, in most cases, inhibition or induction of hepatic and intestinal drug-metabolizing enzymes of the cytochrome P450 family, and/or drug transporters. This chapter provides a review of the potential for herb–drug interactions based on literature reports for those herbs that are most popularly used in the United States. Relevant clinical and human in vitro studies that have evaluated metabolism-based or absorption-based mechanisms to understand the interactions between these herbs and commonly used drugs are also reviewed.