An increasing body of evidence shows that many of the key inositol lipids and enzymes responsible for their metabolism reside in nuclei. Moreover, the association of the nuclear phosphoinositide cycle with progression through the cell cycle and commitment toward differentiation has built a wider picture of the implications of phosphoinositides in the control of nuclear functions. This article reviews a central aspect of inositide nuclear signaling, i.e., the spatial organization of the signaling system within the nucleus in relationship to the nuclear organization in functional domains. Most of the evidence obtained with a variety of confocal and electron microscopy immunocytochemical techniques indicates that the phosphoinositides, the enzymes required for their synthesis and hydrolysis, and the targets of the lipid second messengers are localized at ribonucleoprotein structures involved in the transcript processing in the interchromatin domains. These findings demonstrate that nuclear inositol lipids exist in a nonmembranous form, linked to structural nuclear proteins of the inner nuclear matrix. They also suggest that the inositol signaling in the nucleus is completely independent of that at the cell surface and that it probably preceded in evolution the systems that are present at the cytoskeletal and cell membrane level.