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These mirror\u2010image oligonucleotides have the same physical and chemical properties as that of their native <jats:sc>d<\/jats:sc>\u2010counterparts, yet are highly orthogonal to the stereospecific environment of biology. Consequently, <jats:sc>l<\/jats:sc>\u2010oligonucleotides are resistant to nuclease degradation and many of the off\u2010target interactions that plague traditional <jats:sc>d<\/jats:sc>\u2010oligonucleotide\u2010based technologies; thus making them ideal for biomedical applications. Despite a flurry of interest during the early 1990s, the inability of <jats:sc>d<\/jats:sc>\u2010 and <jats:sc>l<\/jats:sc>\u2010oligonucleotides to form contiguous Watson\u2013Crick base pairs with each other has ultimately led to the perception that <jats:sc>l<\/jats:sc>\u2010oligonucleotides have only limited utility. Recently, however, scientists have begun to uncover novel strategies to harness the bio\u2010orthogonality of <jats:sc>l<\/jats:sc>\u2010oligonucleotides, while overcoming (and even exploiting) their inability to Watson\u2013Crick base pair with the natural polymer. Herein, a brief history of <jats:sc>l<\/jats:sc>\u2010oligonucleotide research is presented and emerging <jats:sc>l<\/jats:sc>\u2010oligonucleotide\u2010based technologies, as well as their applications in research and therapy, are presented.<\/jats:p>","DOI":"10.1002\/chem.201900149","type":"journal-article","created":{"date-parts":[[2019,3,26]],"date-time":"2019-03-26T19:43:21Z","timestamp":1553629401000},"page":"7981-7990","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":91,"title":["Mirror\u2010Image Oligonucleotides: History and Emerging Applications"],"prefix":"10.1002","volume":"25","author":[{"given":"Brian E.","family":"Young","sequence":"first","affiliation":[{"name":"Department of Chemistry Texas A&amp;M University  College Station TX 77843 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandini","family":"Kundu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Texas A&amp;M University  College Station TX 77843 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9275-2597","authenticated-orcid":false,"given":"Jonathan T.","family":"Sczepanski","sequence":"additional","affiliation":[{"name":"Department of Chemistry Texas A&amp;M University  College Station TX 77843 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,4,26]]},"reference":[{"key":"e_1_2_11_1_1","unstructured":"\u00a0"},{"key":"e_1_2_11_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/natrevmats.2017.68"},{"key":"e_1_2_11_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.957"},{"key":"e_1_2_11_4_1","unstructured":"\u00a0"},{"key":"e_1_2_11_5_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2015.070"},{"key":"e_1_2_11_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0026-895X(25)10208-3"},{"key":"e_1_2_11_7_2","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/S0026-895X(25)08583-9","volume":"47","author":"Sands H.","year":"1995","journal-title":"Mol. 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