11 beta-Hydroxysteroid dehydrogenase-type 2 (11 beta-HSD2) regulates the local concentration of cortisol that can activate the glucocorticoid receptor and mineralocorticoid receptor, as well as the concentration of 11-keto-testosterone, the active androgen in fish. Similarly, 17 beta-HSD2 regulates the levels of testosterone and estradiol that activate the androgen receptor and estrogen receptor, respectively. Interestingly, although human 11 beta-HSD2 and 17 beta-HSD2 act at different positions on different steroids, these enzymes are paralogs. Despite the physiological importance of 11 beta-HSD2 and 17 beta-HSD2, details of their origins and divergence from a common ancestor are not known. An opportunity to understand their evolution is presented by the recent sequencing of genomes from sea urchin, a basal deuterostome, and amphioxus, a basal chordate, and the availability of substantial sequence for acorn worm and elephant shark, which together provide a more complete dataset for analysis of the origins of 11 beta-HSD2 and 17 beta-HSD2. BLAST searches find an ancestral sequence of 17 beta-HSD2 in sea urchin, acorn worm and amphioxus, while an ancestral sequence of 11 beta-HSD2 first appears in sharks. Sequence analyses indicate that 17 beta-HSD2 in sea urchin may have a non-enzymatic activity. Evolutionary analyses indicate that if acorn worm 17 beta-H5D2 is catalytically active, then it metabolizes novel substrate(s). (c) 2010 Elsevier Inc. All rights reserved.