The inositol polyphosphate 5-phosphatases selectively remove the phosphate from the 5-position of various phosphatidylinositols, which generate second messengers in response to extracellular signals. The type I inositol polyphosphate 5-phosphatase is predominantly expressed in heart, brain, skeletal muscle, and human placenta. The 5-phosphatase associates with 14-3-3 z, and, in turn, activates the hydrolysis of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. The type II inositol polyphosphate 5-phosphatase encodes a full length protein and a splice variant, which is the predominant form. The 5-phosphatase is ubiquitously expressed, and hydrolyzes inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, and phosphatidylinositol 4,5-bisphosphate. Both type I and II 5-phosphatases are thought to regulate the level of intracellular calcium by acting as signal terminating enzymes.