Recent studies have demonstrated the beneficial effects of arsenic trioxide (ATO) in the treatment of relapsed acute promyelocytic leukemia (APL). The aim of this review is to discuss the role of ATO in the management of APL. Based on the available clinical evidence, a tentative algorithm is proposed for the treatment of patients who relapse after or are refractory to all trans-retinoic acid-based therapy. Other opportunities for the use of ATO in front-line treatment of APL are also discussed, especially its potential use in patients at high risk of relapse and in those with contraindications to chemotherapy or in whom the amount of chemotherapy should be reduced.