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BACKGROUND 2,5-Diketopiperazines (DKPs), also called cyclic dipeptides, are the simplest peptide derivatives in nature that are formed by condensation of two amino acids. They are an important category of bioactive substances with various structures. OBJECTIVE This review focuses on the natural sources, synthetic processes, biological properties and MS fragmentation regularity of simple DKPs, in order to provide a reference for exploring future scientific and therapeutic potentials of these compounds. METHOD Pertinent information was collected and organized from several electronic scientific databases (e.g., Web of Science, China Knowledge Resource Integrated, ScienceDirect, PubMed, Wanfang Data and Google Scholar), PhD and MS dissertations. There are 105 articles published from the early 20th century to 2021 were reviewed in this work. RESULTS DKPs have been obtained from a broad range of natural resources, including fungi, bacteria, plants, and animals, and been synthesized by chemical and biological methods. DKPs have various pharmacological activities, including anticancer, antibacterial, antithrombotic, neuron protective, analgesic, and other activities. Mass spectrometry is the most common method for the structural analysis of DKPs. DKPs can be quickly screened and identified by MS according to the mass spectrum fragmentation pattern of them. CONCLUSION As a category of relatively unexplored compounds, DKPs have been demonstrated to have various bioactivities, especially with antitumor and antibacterial activities. However, the existing research of DKPs is still in the early stage, and their application in drug development needs to be further studied.