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RNA interference technology, using synthetic structurally well\u2010defined short double\u2010stranded RNA (small interfering RNA [siRNA]), has advanced rapidly in recent years. This introductory review describes the utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA\u2010induced silencing complex, siRNAs bind to specific complementary mRNAs, which are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off\u2010target effects. These have been overcome by chemical modification of siRNA and\/or by utilising a range of delivery systems, increasing bioavailability and stability to\u00a0allow successful clinical translation. Patisiran (hereditary transthyretin\u2010mediated amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial hypercholesterolaemia), which all use\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetylgalactosamine (GalNAc) linkage for effective liver\u2010directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non\u2010communicable diseases (hypertension, cancer). Technological advances are paving the way for broader clinical use. Ongoing challenges remain in targeting organs beyond the liver and reaching special sites (e.g., brain). By overcoming these barriers, siRNA therapy has the potential to substantially widen its therapeutic impact.\n                  <\/jats:p>","DOI":"10.1111\/bph.15972","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T04:29:57Z","timestamp":1665980997000},"page":"2697-2720","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":132,"title":["Small interfering RNA: Discovery, pharmacology and clinical development\u2014An introductory review"],"prefix":"10.1111","volume":"180","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1522-9276","authenticated-orcid":false,"given":"Priyanga","family":"Ranasinghe","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine University of Colombo  Colombo Sri Lanka"},{"name":"University\/British Heart Foundation Centre for Cardiovascular Science The University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9577-576X","authenticated-orcid":false,"given":"Melisande L.","family":"Addison","sequence":"additional","affiliation":[{"name":"University\/British Heart Foundation Centre for Cardiovascular Science The University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8630-8625","authenticated-orcid":false,"given":"James W.","family":"Dear","sequence":"additional","affiliation":[{"name":"University\/British Heart Foundation Centre for Cardiovascular Science The University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0755-1756","authenticated-orcid":false,"given":"David J.","family":"Webb","sequence":"additional","affiliation":[{"name":"University\/British Heart Foundation Centre for Cardiovascular Science The University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,13]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1716153"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/10611860903057674"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15538"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15541"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15542"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15537"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15539"},{"key":"e_1_2_14_9_1","unstructured":"Alnylam Pharmaceuticals. 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