Global sales of botanical and other purported medicinal natural products (NPs) continue to rise, increasing the risk for adverse interactions with co-consumed conventional drugs, potentially leading to suboptimal therapeutic outcomes. Unlike for drug-drug interactions, rigorous guidelines for assessing NP-drug interactions are nonexistent. A multidisciplinary effort involving drug metabolism/pharmacokinetic scientists, clinical pharmacologists, NP chemists, and health informaticists is needed to develop rigorous guidelines for assessing and disseminating the drug interaction liability of NPs. Such guidelines should lead to improved design of future in vitro and clinical NP-drug interaction studies and ultimately, evidenced-based information regarding the optimal management of these complex interactions.