Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As(2)O(3)) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RAR alpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RAR alpha degradation is triggered by their SUMOylation, but the mechanism by which As(2)O(3) induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RAR alpha and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As(2)O(3) provides new insights into the drug's mechanism of action and its specificity for APL.