Evidence accumulated over the past 20 years has highlighted the presence of an autonomous nuclear inositol lipid metabolism, and suggests that lipid signalling molecules are important components of signalling pathways operating within the nucleus. Nuclear polyphosphoinositide (PI) signalling relies on the synthesis and metabolism of phosphatidylinositol 4,5-bisphosphate, which can modulate the activity of effector proteins and is a substrate of signalling enzymes. The regulation of the nuclear PI pool is totally independent from the plasma membrane counterpart, suggesting that the nucleus constitutes a functionally distinct compartment of inositol lipids metabolism. Among the nuclear enzymes involved in PI metabolism, inositide specific phospholipase C (PI-PLC) has been one of the most extensively studied. Several isoforms of PI-PLCs have been identified in the nucleus, namely PI-PLC-β1, γ1, δ1 and ζ; however, the β1 isozyme is the best characterized. In the present review, we focus on the signal transduction-related metabolism of nuclear PI-PLC and review the most convincing evidence for PI-PLC expression and activity being involved in differentiation and proliferation programmes in several cell systems. Moreover, nuclear PI-PLC is an intermediate effector and interactor for nuclear inositide signalling. The inositide cycle exists and shows a biological role inside the nucleus. It is an autonomous lipid-dependent signalling system, independently regulated with respect to the one at the plasma membrane counterpart, and is involved in cell cycle progression and differentiation.