Nuclear phosphoinositide-phospholipase C (PI-PLC) beta1 plays a crucial role in the molecular steps that regulate cell proliferation and differentiation in several experimental models, such as myoblasts and hematopoietic cells, via interaction with other important molecular players. Indeed, PI-PLCbeta1 and its related molecules are definitely involved in hematopoiesis, and particularly in drug-induced myeloid or erythroid differentiation. Here, we review the role of nuclear PI-PLCbeta1 signalling in normal hematopoiesis, in pathogenesis and in drug-related induction of hematopoietic differentiation, with particular reference to the current therapy of Myelodysplastic Syndromes (MDS).