Phosphatidylinositol‐specific phospholipase C (PI‐PLC) enzymes are a family of receptor‐regulated phosphodiesterases that control many cellular processes by the regulation of cytosolic calcium and/or the activity of several protein kinases. Recently we identified a seventh class of PI‐PLC enzymes (called PLC‐XDs), which contains only the catalytic X domain of the normal multi‐domain‐ containing enzyme family. Three tissue‐specific PLC‐XD isoforms exist in humans, hPLC‐XD1, ‐XD2 and ‐XD3, with ‐XD2 exhibiting three C‐terminal spliceforms. Similar PLC‐XD orthologs have been identified in mice with the mPLC‐XD3 having two C‐terminal spliceforms. PLC‐XD isoforms exhibited their own individual tissue‐specific expression profiles and sub‐cellular localisations with some similarities between species. PLC‐XD1 and ‐XD3 isoforms were expressed in most tissues tested with PLC‐XD2 mainly found in leucocytes and thymus in humans, but predominately in the GI‐tract and stomach of mice. PLC‐XD3, which exhibits the highest sequence homology across species, was mainly expressed in mouse and human heart. The expression profiles suggest that these novel proteins may possess fundamental, and as yet uncharacterised tissue‐specific roles in cell physiology.Funding: School of Medicine, University of St Andrews