ETHNOPHARMACOLOGICAL RELEVANCE: Punica granatum L. (Punicaceae) has been used for centuries in many cultures for the prevention and treatment of a wide number of health disorders such as inflammation, diabetes, diarrhea, dysentery, dental plaque and to combat intestinal infections and malarial parasites. AIM OF THE REVIEW: This review aims at providing an up-to-date overview of the chemical constituents, traditional uses, phytochemistry, pharmacology and toxicology of Punica granatum L. Moreover, the focus of this review is the possible exploitation of this species to treat different diseases and to suggest future investigations. MATERIALS AND METHODS: An extensive and systematic review of the extant literature was carried out, and the data under various sections were identified by using a computerized bibliographic search via PubMed, Web of Science and Google Scholar. All abstracts and full-text articles were examined. The most relevant articles were selected for screening and inclusion in this review. KEY FINDINGS: A variety of pomegranate ethnomedical uses have been recorded. Additionally, over the last decade, there has been a dramatic increase of interest in pomegranate as a medicinal and nutritional product due to its newly identified potential health effects, which include treatment and prevention of cancer and cardiovascular diseases. From the toxicological perspective, pomegranate fruit juice, extracts and preparations have been proven to be safe. CONCLUSIONS: The ethnopharmacological relevance of pomegranate is fully justified by the most recent findings indicating the fruit is a medicinal and nutritional agent useful for treating a wide range of human disorders and maladies. Further investigations are needed to fully understand the mode of action of the active constituents and to fully exploit pomegranate's preventive and therapeutic potential.