8-Oxo-2'-deoxyguanosine (OdG) is a prominent DNA damaged nucleotide that is a known promutagen and has been linked to cancer and aging. To limit the harmful effects of OdG, E. coli and human cells have evolved repair glycosylases, Fpg (MutM) and hOGG, respectively, that remove the 8-oxoguanine base from OdG:dC base pairs. Though much research has focused on the mode of substrate recognition by these enzymes, many unanswered questions have remained. Herein we report that both enzymes are active on a wide array of dG/OdG analogues that vary in their composition within the imidazole ring. These findings suggest that Fpg and hOGG recognize their substrate, at least in part, based on the lack of a lone pair at a fully sp(2)-hybridized N7.