Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)] is a minor lipid of the inner leaflet of the plasma membrane that controls the activity of numerous proteins and serves as a source of second messengers. This multifunctionality of PI(4,5)P(2) relies on mechanisms ensuring transient appearance of PI(4,5)P(2) clusters in the plasma membrane. One such mechanism involves phosphorylation of PI(4)P to PI(4,5)P(2) by the type I phosphatidylinositol-4-phosphate 5-kinases (PIP5KI) at discrete membrane locations coupled with PI(4)P delivery/synthesis at the plasma membrane. Simultaneously, both PI(4)P and PI(4,5)P(2) participate in anchoring PIP5KI at the plasma membrane via electrostatic bonds. PIP5KI isoforms are also selectively recruited and activated at the plasma membrane by Rac1, talin, or AP-2 to generate PI(4,5)P(2) in ruffles and lamellipodia, focal contacts, and clathrin-coated pits. In addition, PI(4,5)P(2) can accumulate at sphingolipid/cholesterol-based rafts following activation of distinct membrane receptors or be sequestered in a reversible manner due to electrostatic constrains posed by proteins like MARCKS.