We review the role of all-trans retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL). The combination of ATRA and conventional anthracycline-ARA-C chemotherapy (CT) has clearly demonstrated its superiority over CT alone (in terms of relapse and survival) in newly diagnosed APL. Combination treatment probably also reduces the incidence of initial failures, and complete remission (CR) rates greater than 90% are now regularly reported in large multicenter trials. Some randomized studies strongly suggest that prolonged maintenance treatment (for 1 or 2 years) with ATRA and low-dose CT, and possibly very early introduction of anthracycline CT during induction treatment, may reduce the incidence of relapse. With those treatments, the relapse risk appears to be only 10%-15%, although it remains greater in patients who initially have high white blood cell counts (often associated with variant M3 morphology, short bcr3 isoform, etc.) and patients with residual disease detectable by RT-PCR at the end of consolidation courses. In those patients, addition of arsenic derivatives to induction or consolidation treatment (or both treatments together) may prove useful and is currently being tested. ATRA syndrome (now generally called APL differentiation syndrome, as it is also seen with arsenic derivatives) remains the major side effect of ATRA treatment. It occurs in 10%-15% of patients and is currently fatal in at least 10% of them. Rapid onset of CT or high dose steroids (or both) should improve its outcome. A sizeable proportion of APL patients who relapse after ATRA and CT can be durably salvaged by the same treatment followed by allogeneic or autologous stem cell transplantation, provided the transplant (in the autologous setting) is RT-PCR-negative. However, in relapsing APL arsenic derivatives (mainly arsenic trioxide) are now considered to be the reference treatment. Some of the current issues with ATRA treatment in newly diagnosed APL include whether ATRA has a role during consolidation treatment and whether arabinoside (AraC) is required in addition to anthracyclines in the chemotherapy combined to ATRA.