DNA-encoded libraries (DELs) are useful for hit discovery in the pharmaceutical industry. Although a large number of individually coded molecules are accessible through DELs, their structural diversity is limited because few transformations are benign and chemoselective enough to be applied in the presence of DNA in aqueous environments. In particular, C-H functionalization chemistry that could be ideally suited to increase structural diversity through late-stage functionalization is currently absent from DEL synthesis. Here we present a general C-H functionalization of electron-rich arenes on DNA. The development of a selenoxide reagent is key to achieving the regio- and chemoselective formation of arylselenonium salts in aqueous media. The introduction of arylselenonium salts offers a versatile linchpin on DNA conjugates, which gives access to a multitude of analogues through diverse subsequent reactions, including transition-metal-mediated and photochemical transformations for the formation of C-C, C-I and C-S bonds.