In an article published by Helvetica Chimica Acta in 1995, chemist P. Martin describes the synthesis of 2′-O-alkylated ribonucleosides for use in therapeutic antisense oligonucleotides (ASOs). This work was motivated by the need for a modified ribose structure that was compatible with solid-phase synthesis protocols and that, when incorporated into an oligonucleotide, would render it resistant to nucleases without attenuating its ability to hybridize to a complementary RNA target. Martin described a robust route to 2′-O-alkylribonucleosides in which the ribose 2′-OH group is substituted with 2′-ethylene glycol derivatives. Oligonucleotides containing these modifications displayed überraschende Eigenschaften – ‘surprising properties’ – notably, higher affinity and specificity for RNA substrates and greater stability to nucleases relative to their unmodified counterparts. Today, the 2′-ethylene glycol modification is universally known in the field as the 2′-O-methoxyethyl (MOE) modification. The chemistry features in four ASO drugs and many others in clinical trials. Here, we 1) summarize the synthesis of the MOE-modified ribose; 2) outline the properties of MOE-modified oligonucleotides as reported in Martin’s article; 3) highlight the first approved MOE-modified ASO drugs, mipomersen and nusinersen; and 4) survey MOE-modified ASOs in clinical development. In the outlook, we put these developments into context and consider future possibilities for the MOE modification.