Phosphotidylinositols (Pis) are known to play an essential role in membrane trafficking and signaling transduction. PIs serve multiple functions, such as recruitment of cytosolic proteins with PI phosphate (PIP) binding domains and modification of the physical properties of the membranes in which they reside. As substrates for phosphoinositide-specific lipases they function as a switch point in phosphoinositide metabolism. Recent work with epidermal growth factor receptor (EGFR) and colony stimulating factor-1 receptor (CSFR) has identified a possible connection between endocytosis of activated receptors and type-1 phosphatidylinositol-4-phosphate-5-kinase. Furthermore, serine/tyrosine phosphorylation of phosphatidylinositol-4-phosphate-5-kinase seems to be essential for its activities. Indeed, one of the products of the phosphatidylinositol-4-phosphate-5-kinases, PIP2, has been shown to be involved in multiple steps of endocytosis, including the assembly of the clathrin coat, regulation of adaptor proteins, and production of endocytic vesicles via the regulation of dynamin. The discussion in this review focuses primarily on receptors with intrinsic enzymatic activity, specifically on receptor tyrosine kinases (RTKs). We will discuss their structure; mechanism of action and potential role in membrane trafficking and/or signaling through the regulation of phosphatidylinositol phosphate kinases.