The PML::RARα fusion protein drives all the morphological variants of t(15;17) APL by disrupting nuclear bodies and blocking myeloid cell differentiation at the promyelocyte stage. Arsenic and ATRA target the PML and RARα components of the fusion protein, respectively. ATRA binds to the ligand binding domain (LBD) of RARα and induces conformational change, releasing corepressors and activating transcription of target genes involved in myeloid differentiation. As(III), the active component of arsenic trioxide, binds a pocket formed by C213 residues in PML B-box 2 trimers and induces a cascade of events resulting in nuclear body reformation, PML and PML::RARα sumoylation, polyubiquitination, and proteasomal degradation. Cellular images courtesy of the ASH Image Bank (image IDs #00005911, #00063635, and #00003608). Professional illustration by Patrick Lane, ScEYEnce Studios.