Leukocyte alkaline phosphatase (LAP) is the product of the gene coding for the liver/bone/kidney-type alkaline phosphatase. In the normal hematopoietic system, the only cell type expressing LAP in basal conditions is the post-mitotic neutrophilic granulocyte. Thus LAP represents a specific and restrictive marker for the terminal maturation of the neutrophilic granulocyte. The study of the factors and the molecular mechanisms responsible for the expression of LAP in cells undergoing granulocytic maturation may shed light on this complex biological process. Acute promyelocytic leukemia (APL) represents a unique biological model in which it is possible to investigate neutrophilic differentiation. APL blasts undergo rapid and irreversible maturation towards cells morphologically and biochemically resembling normal mature granulocytes upon in vivo and in vitro challenge with all-trans retinoic acid (ATRA). In this cellular context, we studied the endogenous factors involved in the expression of LAP. The phosphatase is not synthesized in undifferentiated APL blasts and it is expressed only upon treatment with combinations between ATRA and a second cyto-differentiating signal. The second signal may be given by G-CSF, cAMP analogs, IL-6 and to a lesser extent by IL-1 beta. The molecular mechanisms underlying the induction of LAP by combinations of ATRA and G-CSF or cAMP analogs were studied in detail and are the object of this review.