The Japanese Society of Gastroenterology (JSGE) first published evidence-based clinical practice guidelines for cholelithiasis in 2010, followed by a revision in 2016. In April 2023, JSGE published the 2021 edition of evidence-based clinical practice guidelines for cholelithiasis based on the clinical issues associated with cholelithiasis in the databases such as Medline, Cochrane, and Igaku Chuo Zasshi and the latest evidence in literature published in the past five years. The revised edition reviews related clinical questions in the previous edition from the aspects of the epidemiology, pathogenesis, diagnosis, treatment, prognosis, and complications of cholelithiasis and reclassifies them into three categories, with 52 questions in total, among which there are 29 background questions dealing with basic background knowledge, 19 clinical questions, and 4 future research questions requiring further accumulation of evidence, thereby providing guidance for decision making in the clinical management of patients with cholelithiasis.