Prokaryotic and eukaryotic fumarylacetoacetate hydrolase (FAH) superfamily members, sharing conserved regions that form the so-called FAH-domain, catalyze a remarkable variety of reactions. These enzymes are essential in the metabolic pathways to degrade aromatic compounds in prokaryotes and eukaryotes. It appears that prokaryotic FAH superfamily members evolved mainly to allow microbes to generate energy and useful metabolites from complex carbon sources. We review recent findings, indicating that both prokaryotic and eukaryotic members of the FAH superfamily also display oxaloacetate decarboxylase (ODx) activity. The identification of human FAH domain-containing protein 1 as mitochondrial ODx regulating mitochondrial function supports the new concept that, during evolution, eukaryotic FAH superfamily members have acquired important regulatory functions beyond catabolism of complex carbon sources. Molecular studies on the evolution and function of FAH superfamily members are expected to provide new mechanistic insights in their physiological roles.