Nature Chemistry, Published online: 22 July 2026; doi:10.1038/s41557-026-02214-6 Oligonucleotide modification largely relies on unstable, expensive phosphoramidite reagents, limiting the diversity and efficiency of chemical functionalization. Now, a site-selective modification of synthetic oligonucleotides is reported via the in situ generation of phosphoramidites on the solid-supported oligonucleotide. This approach enables cost-effective and versatile modification of oligonucleotides, including terminal and internal modifications.