Carbonic Anhydrase isoform XIV (CA XIV) is the last member of the human (h) CA family discovered so far, being localized in brain, kidneys, colon, small intestine, urinary bladder, liver and spinal cord. It has recently been described as a possible drug target for treatment of epilepsy, some retinopathies as well as some skin tumors. hCA XIV is a membrane-associated protein consisting of an N-terminal extracellular domain, a putative transmembrane region and a small cytoplasmic tail. In this paper we report the expression, purification and the crystallographic structure of the entire extracellular domain of this enzyme. The analysis of the structure revealed the typical α-CA fold, in which a ten-stranded β-sheet forms the core of the molecule, while the comparison with all the other membrane associated isoforms (hCA IV, IX and XII) allowed to identify the diverse oligomeric arrangement and the sequence and structural differences observed in the region 127-136 as the main factors to consider in the design of selective inhibitors for each one of the membrane associated α-CAs.