<p>Strategic single-atom substitution has the potential to accelerate drug development by facilitating the generation of matched molecular counterparts. However, systematic evaluation of single-atom effects often faces considerable synthetic challenges, primarily because of the limited accessibility of direct atomic exchange pathways. Here we present a skeletal editing strategy that enables the direct conversion of oxazoles and isoxazoles into thiazoles and isothiazoles, respectively, using different catalytic approaches. For isoxazoles, we used iron-catalysed single-atom substitution with Lawesson’s reagent, enabling a straightforward oxygen-to-sulfur transformation. In contrast, oxazoles use a Lewis acid (La(OTf)₃) for the same substitution, highlighting distinct reaction mechanisms. Both strategies allow for the rapid diversification of bioactive compounds, generating complex thio-analogues with broad functional group compatibility, thus streamlining synthesis and potential structure–activity relationship studies. The developed methods expand the toolkit for skeletal editing, and provide advantages for pharmaceutical research and development.</p><p></p>