In only few decades, remarkable advances in biology and therapy have transformed acute promyelocytic leukemia (APL), once regarded as the most rapidly fatal human leukemia, into a paradigm of targeted treatment in human cancer, with most patients being nowadays curable without any or with only small amounts of conventional chemotherapy. Yet, the management of this rare subtype of leukemia remains today highly challenging, due to its aggressive presenting features and to some peculiar disease-and treatment-related complications. The APL-unique t (15; 17) translocation, which generates the PML/RARA oncoprotein is the key pathogenetic event of APL. This hybrid protein results in the differentiation block of bone marrow myeloid precursors and is responsible for the exquisite sensitivity of the disease to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Mechanistically, PML/RARA acts as an aberrant retinoic acid receptor alpha (RARA) and displays an increased affinity for the chromatin remodeling and methylating enzymes leading to transcriptional repression of genes critical for myeloid differentiation. ATRA induces terminal differentiation of leukemic promyelocytes by binding RARA and inducing the transcriptional reactivation of target genes repressed by PML/RARA as well as the direct degradation of the oncoprotein. ATO in turn targets PML/RARA by binding to its PML moiety and induces the degradation of the oncoprotein, thus restoring the formation of matrix-associated nuclear bodies, finally resulting in APL cell death (Figure 1)[1]. Due to the severe bleeding diathesis frequently present at diagnosis, APL remains one of the most aggressive forms of leukemia and has to be managed as a medical emergency. Institution of supportive care (ie platelets, fibrinogen and/or fresh frozen plasma transfusions) together with prompt initiation of ATRA must immediately follow the clinical suspect of APL [2]. However, genetic diagnostic confirmation to identify PML/RARA is mandatory and can be readily obtained by FISH or PCR testing in leukemic blood or (preferably) bone marrow cells. The bleeding tendency due to an imbalance between procoagulant, anticoagulant, and fibrinolytic activities is triggered by circulating APL cells and can cause lethal hemorrhagic events within the first hours or days from diagnosis or sometimes even before APL diagnosis is suspected. Differentiation induced by ATRA results in the loss of procoagulant and fibrinolytic properties of APL cells, with improvement of the hypercoagulable state [3]. APL is classified as low/intermediate-or highrisk according to the platelet (PLT) and white blood cell (WBC) counts at the time of initial diagnosis (ie PLT< or> 40x109/L, and WBC> 10x109/L, respectively). This classification reflects disease severity, but it is not clear whether high-risk APL represents an advanced disease phase or a distinct biological disease subset. Until recently, ATRA combined to anthracyclines has been the standard of care for newly diagnosed patients.[2] For low/intermediate risk APL, a chemotherapy-free regimen combining ATO and ATRA has been shown to be superior