Growth, differentiation, and apoptosis of eukaryotic cells are mediated by extremely complex signaling pathways and a high degree of coordination is required for regulating cell proliferation. In multicellular organisms homeostasis is achieved through signal transduction events. If these homeostatic mechanisms are interrupted, a disease, such as cancer, may ensue. Lipid second messengers, particularly those derived from polyphosphoinositide cycle, play a pivotal role in several cell signaling networks. Evidence accumulated over the past 15 years has highlighted the presence of an autonomous nuclear inositol lipid metabolism, and suggests that lipid signaling molecules are important components of signaling pathways operating within the nucleus. Recent findings are starting to elucidate how the nuclear phosphoinositide cycle is regulated and what down-stream molecules are targeted through this cycle. In this review, we shall summarize the most updated data about inositol lipid-dependent nuclear signaling pathways that might have a relevance for the development of cancer. In the near future, this knowledge might also prove to have relevance for the diagnosis and treatment of the neoplastic disease.