Evolution generated a vast structural and mechanistic diversity to accomplish this reaction. Enzymatic decarboxylation reactions encompass both oxidative and non-oxidative reactions via heterolytic and homolytic mechanisms, and employ diverse cofactors. These include pyridoxal phosphate, thiamine diphosphate, the pyruvoyl group, heme as well as non-heme diiron centers, and even FAD in a photobiocatalytic reaction. In contrast, only three decarboxylases are known to catalyze decarboxylations without a cofactor. Orotidine-5′-monophosphate decarboxylase, bacterial phenolic acid decarboxylase, and arylmalonate decarboxylase stabilize the evolving carbanion in the transition state without the delocalization into a cofactor-system. They achieve this stabilization by acid-base catalysis and the assistance of the substrate as an intermediary electron sink. In this paper, we propose a fourth mechanistic principle for cofactor-free decarboxylation by enzymes (Figure ).