The year 2023 marks the 25^th anniversary of the discovery of RNA interference (RNAi). RNAi-based therapeutics enable sequence-specific gene knockdown by eliminating target RNA molecules through complementary base-pairing. A systematic review of published and ongoing clinical trials was performed. Web of Science, PubMed, and EMBASE were searched from January 1, 1998, to December 30, 2022 for clinical trials utilizing RNAi. Following inclusion, data from the articles were extracted according to a predefined protocol. A total of 90 trials published in 81 articles were included. In addition, ongoing clinical trials were retrieved from ClinicalTrials.gov, resulting in inclusion of 48 trials. We investigated how maturation of RNAi-based therapeutics and developments in delivery platforms, administration routes, and potential targets shape the current landscape of clinically applied RNAi. Notably, most contemporary clinical trials used either N-acetylgalactosamine-delivery and subcutaneous administration or lipid-NP-delivery and intravenous administration. In conclusion, RNAi therapeutics have gained great momentum during the last decade, resulting in five approved therapeutics targeting the liver for treatment of severe diseases, and the trajectory depicted by the ongoing trials emphasize that even more RNAi-based medicine also targeting extra-hepatic tissues are likely to be availed in the years to come.