The cytosolic isoform XIII is a recently discovered member of the human carbonic anhydrase (hCA, EC 18.104.22.168) family. It is selectively expressed among other tissues in the reproductive organs, where it may control pH and ion balance regulation, ensuring thus proper fertilization conditions. The authors report here the X-ray crystallographic structure of this isozyme in the unbound state and in complex with a classical sulfonamide inhibitor, namely acetazolamide. A detailed comparison of the obtained structural data with those already reported for other CA isozymes provides novel insights into the catalytic properties of the members of this protein family. On the basis of the inhibitory properties of acetazolamide against various cytosolic/transmembrane isoforms and the structural differences detected within the active site of the various CA isoforms, further prospects for the design of isozyme-specific CA inhibitors are here proposed. Proteins 2009.