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Expanding the chemical repertoire of aptamers Aptamers offer distinct advantages over conventional small molecules or antibodies due to their high affinity and specificity. Additional benefits, including small size and ease of modification, further enhance their biomedical potential. Nonetheless, their interaction capabilities remain constrained by the limited chemical diversity of natural nucleobases, restricting the repertoire of targets accessible in vitro and in vivo. This review highlights strategies to overcome these limitations by expanding the chemical diversity of aptamers, including sugar, backbone, and nucleobase modifications, as well as selection approaches for their identification. We discuss structural insights into modified aptamers and explain their potential in practical applications. Finally, key challenges are identified that must be addressed to fully achieve the therapeutic and diagnostic utility of chemically modified aptamers. http://dlvr.it/TPfn55