Ethnopharmacological Relevance: The genus Dioscorea, a member of the Dioscoreaceae family, comprises approximately 600 species and is widely distributed across temperate and tropical regions such as Asia, South Africa, and North America. The traditional medicinal uses of Dioscorea have been documented in Asian and African pharmacological systems. In Asia, this genus is traditionally used to treat respiratory illnesses, rheumatism, diabetes, diarrhea, dysentery, and other conditions. In Africa, this genus has been used to treat human immunodeficiency virus and ring worms. However, the traditional medicinal practices in North America rarely mention the use of this genus., Aim of the Study: The aim of this review is to comprehensively review the genus Dioscorea, focusing on its traditional uses, phytochemical constituents, pharmacological activities, and potential toxicities. The research also aims to highlight the valuable bioactive compounds within Dioscorea and emphasize the need for further investigations into acute and chronic toxicity, activity mechanisms, molecular markers, and other relevant factors to contribute to the discovery of novel pharmaceuticals., Materials and Methods: A search for available information on Dioscorea was conducted using scientific databases, including PubMed, ISI-WOS, Scopus, and Google Scholar, as well as recent academic publications from reputable publishers and other literature sources. The search was not limited by language and spanned the literature published between 1950 and 2022., Results: This article provides a comprehensive review of the Dioscorea genus, focusing on its traditional uses, phytochemical constituents, pharmacological activities, and potential toxicities. Extensive research has been conducted on this genus, resulting in the isolation and examination of over 1000 compounds, including steroids, terpenoids, and flavonoids, to determine their biological activities. These activities include anti-tumor, anti-inflammatory, immunomodulatory, neuroprotective, hypoglycemic, and hypolipidemic effects. However, some studies have indicated the potential toxicity of high doses of Dioscorea, highlighting the need for further investigations to assess the safety of this genus. Additionally, this review explores potential avenues for future research and discusses the challenges associated with a comprehensive understanding of the Dioscorea genus., Conclusions: Based on the existing literature, it can be concluded that Dioscorea is a valuable source of bioactive compounds that have the potential to treat various disorders. Future research should prioritize the investigation of acute and chronic toxicity, activity mechanisms, molecular markers, and other relevant factors. This review provides a comprehensive analysis of the Dioscorea genus, emphasizing its potential to enable a deeper exploration of the biological activity mechanisms of these plants and contribute to the discovery of novel pharmaceuticals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)