A spontaneous thiol-ene polymerization has been reported in the literature for a broad range of monomers, generally under conditions avoiding solvent, heating and the intentional formation of radicals. In the search for a mechanism accountable to self-initiated thiol-ene polymerization, this study demonstrates the significant role played by thiyl radicals produced by thiol oxidation through dissolved atmospheric oxygen in the thiol-ene mixture. To determine the factors underlying the reactivity, self-initiated polymerization kinetics, thiol solvation and the nature of initiating radicals are studied by means of various techniques including real-time FTIR, 1 H NMR spectroscopy and spin-trapping experiments. Our data support that the driving force for thiol air oxidation is the polarization of the S-H bond. Thiol substituents with electron-withdrawing properties and/or hydrogen-bonded thiol-solvent (or thiol-alkene) complexes favor self-initiation by increasing S-H bond polarization, thereby easing an electron transfer to molecular oxygen.