It is now possible to compare life forms at high levels of detail and completeness due to the increasing availability of whole genomes from all three domains. However, exploration of interesting hypotheses requires the ability to recognize a correspondence between proteins that may since have diverged beyond the threshold of detection by sequence-based methods. Since protein structure is far better conserved than protein sequence, structural information can enhance detection sensitivity, and this is the basis for the field of structural genomics. Demonstrating the effectiveness of this approach, we identify two important but previously elusive Archaeal enzymes: a homolog of dihydropteroate synthase and a thymidylate synthase. The former is especially noteworthy in that no Archaeal homolog of a bacterial folate biosynthetic enzyme has been found to date. Experimental confirmation of the deduced activity of both enzymes is described. Identification of two different proteins was attempted deliberately to help allay concern that predictive success is merely a lucky accident.