Paeonia, which comprises approximately 52 shrubs or herbaceous perennials around the world, is the only genus of the Paeoniaceae and is pervasively distributed in Asia, southern Europe, and North America. Many species of the genus Paeonia have been used for centuries in ethnomedical medical systems. The present study aims to summarize the traditional uses, clinical applications, and toxicology of the genus Paeonia, to critically evaluate the state-of-the-art phytochemical and pharmacological studies of this genus published between 2011 and 2020, and to suggest directions for further in-depth research on Paeonia medicinal resources. Popular and widely used databases such as PubMed, Scopus, Science Direct, and Google Scholar were searched using the various search strings; from these searches, a number of citations related to the traditional uses, phytochemistry, biological activities, clinical application, and toxicology of the genus Paeonia were retrieved. The use of 21 species, 2 subspecies, and 7 varieties of the genus Paeonia as traditional herbal remedies has been reported, and many ethnomedicinal uses, such as the treatment of hematemesis, blood stasis, dysmenorrhea, amenorrhea, epilepsy, spasms, and gastritis, have been recorded. The roots and root bark are the most frequently reported parts of the plants used in medicinal applications. In phytochemical investigations, 451 compounds have been isolated from Paeonia plants to date, which contains monoterpenoid glucosides, flavonoids, tannins, stilbenes, triterpenoids and steroids, and phenols. Studies of their pharmacological activities have revealed the antioxidant, anti-inflammatory, antitumour, antibacterial, antiviral, cardiovascular protective, and neuroprotective properties of the genus Paeonia. In particular, some bioactive extracts and compounds (total glucosides of peony (TGP), paeonol, and paeoniflorin) have been used as therapeutic drugs or tested in clinical trials. In addition to the "incompatibility" of the combined use of "shaoyao" and Veratrum nigrum L. roots in traditional Chinese medicine theory, Paeonia was considered to have no obvious toxicity based on the available toxicological tests. A large number of phytochemical and pharmacological reports have indicated that Paeonia is an important medicinal herb resource, and some of its traditional uses including the treatment of inflammation and cardiovascular diseases and its use as a neuroprotective agent, have been partially confirmed through modern pharmacological studies. Monoterpenoid glucosides are the main active constituents. Although many compounds have been isolated from Paeonia plants, the biological activities of only a few of these compounds (paeoniflorin, paeonol, and TGP) have been extensively investigated. Some paeoniflorin structural analogues and resveratrol oligomers have been preliminarily studied. With the exception of several species (P. suffruticosa, P. ostii, P. lactiflora, and P. emodi) that are commonly used in folk medicine, many medicinal species within the genus do not receive adequate attention. Conducting phytochemical and pharmacological experiments on these species can provide new clues that may lead to the discovery of medicinal resources. It is necessary to identify the effective phytoconstituents of crude extracts of Paeonia that displayed pharmacological activities by bioactivity-guided isolation. In addition, comprehensive plant quality control, and toxicology and pharmacokinetic studies are needed in the future studies. Copyright © 2020 Elsevier B.V. All rights reserved.