Phosphoinositide signaling pathways regulate many essential cellular functions including proliferation, differentiation and survival, cytoskeletal organization, and vesicular trafficking. The inositol polyphosphate 5‐phosphatases regulate the cellular levels of several bioactive phosphoinositide species. This review describes the structure and function of the 5‐phosphatase and Sac1 catalytic domains of these enzymes. The crystal structure of the 5‐phosphatase domain has been solved and shares homology with members of the AP endonuclease family. The phosphoinositide polyphosphatase activity of the Sac1 domain, found in some inositol polyphosphate 5‐phosphatases, is defined by a motif, CX 5 R(T/S), also found in both protein and lipid phosphatases.