Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the PML/RARA oncogene. The prognosis for patients with APL was revolutionized by two treatments: retinoic acid (RA) and As₂O₃ (arsenic trioxide). These were both shown a posteriori to target PML/RARA, explaining their exquisite specificity for APL. Arsenic, as a single agent, cures up to 70% of patients, whereas APL patients treated with the combination of RA and As₂O₃ reach a stunning 90% cure rate. Recent physiopathological models highlight the key role of RA- and As₂O₃-triggered PML/RARA degradation, and the molecular mechanisms underlying As₂O₃-induced PML/RARA degradation have been recently clarified. As discussed below, arsenic binding, oxidation, sumoylation on PML nuclear bodies, and RNF4-mediated ubiquitination all contribute to the As₂O₃-triggered catabolism of PML/RARA.