Objectives: To set out the second in a series of guidelines on the treatment of urolithiasis by the International Alliance of Urolithiasis that concerns retrograde intrarenal surgery (RIRS), with the aim of providing a clinical framework for urologists performing RIRS. Materials and Methods: After a comprehensive search of RIRS-related literature published between 1 January 1964 and 1 October 2021 from the PubMed database, systematic review and assessment were performed to inform a series of recommendations, which were graded using modified GRADE methodology. Additionally, quality of evidence was classified using a modification of the Oxford Centre for Evidence-Based Medicine Levels of Evidence system. Finally, related comments were provided. Results: A total of 36 recommendations were developed and graded that covered the following topics: indications and contraindications; preoperative imaging; preoperative ureteric stenting; preoperative medications; peri-operative antibiotics; management of antithrombotic therapy; anaesthesia; patient positioning; equipment; lithotripsy; exit strategy; and complications. Conclusion: The series of recommendations regarding RIRS, along with the related commentary and supporting documentation, offered here should help provide safe and effective performance of RIRS.