Phosphatidylinositol 4,5-bisphosphate (PIP2) is a prevalent phosphoinositide in the inner leaflet of the plasma membrane. PIP2 associates with an ever-growing list of proteins, and participates in a variety of cellular processes. PIP2 signaling to the actin cytoskeleton transduces specific signals necessary for changes in morphology, motility, endocytosis, exocytosis, phagocytosis, and cell activation. The mechanism(s) by which PIP2 signaling pathways are specific is a topic of intense investigation. One working model is the compartmentalization of PIP2-mediated signaling by concentrating PIP2 in cholesterol-dependent membrane rafts, therefore providing spatial and temporal regulation. Here we discuss properties of PIP2 signaling to the actin cytoskeleton in immune cell functioning, the association of PIP2 cellular pools with membrane rafts, and recent work investigating models for compartmentalization of PIP2-mediated signaling in membrane rafts to the actin cytoskeleton.