Over the last decades, evidence has accumulated suggesting that there is a distinct nuclear phosphatidylinositol pathway. One of the best examined nuclear lipid pathways is the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI4,5P(2)) by PLC resulting in activation of nuclear PKC and production of inositol polyphosphates. However, there is a growing number of data that phosphoinositides are not only precursor for soluble inositol phosphates and diacylglycerol, instead they can act as second messengers themselves. They have been implicated to play a role in different important nuclear signaling events such as cell cycle progression, apoptosis, chromatin remodeling, transcriptional regulation and mRNA processing. This review focuses on the role of specifically PI4,5P(2) in the nucleus as a second messenger as well as a precursor for PI3,4,5P3, inositol polyphosphates and diacylglycerol.