Herbal product usage in the North American population continues to increase across all age groups. This population has ready access to conventional medications, with significant polypharmacy observed in older adults. Patients are reticent to disclose herbal product usage to their healthcare providers, and many providers still do not inquire about such usage. Dietary supplements, including herbal products, are not subject to the same regulatory guidelines for pre-market testing as drugs. Considerations such as history of safe use, literature data from toxicity studies, and constituent amounts in products may provide guidance on whether to assess HDIs experimentally. The literature is replete with reports of various herbal extracts and constituents as potent inhibitors of drug metabolizing enzymes, including the cytochromes P450. However, without the use of standard methods for herbal product characterization or in vitro testing, extrapolating these reports to clinically-relevant HDIs is difficult. This lack of a clear definition of risk prevents clinicians and consumers from making informed decisions about the safety of taking herbal products with conventional medications. A logical strategy is to borrow, as applicable, from the testing guidances for assessing drug-drug interactions established by regulatory agencies (e.g., FDA, EMA). For example, intestinal and hepatic in vitro systems can be used to assess potential HDIs. These data can be incorporated into PBPK models to help determine clinical relevance. In summary, a framework is needed that describes a flexible approach for assessing when HDI studies are warranted and an outline of standard methods when HDI testing is conducted.