Acute promyelocytic leukemia (APL), a highly curable subtype of acute myeloid leukemia (AML) is characterized by the chromosomal translocation t(15;17) and, consequently, the presence of the PML-RARalpha fusion transcript. Most patients are treated with all-trans retinoic acid (ATRA), which targets the RAR-alpha moiety of the PML/RAR-alpha fusion transcript, and anthracycline-based chemotherapy. Arsenic trioxide (ATO) targets the PML moiety and has different mechanisms of action at different concentrations, and induces differentiation and apoptosis. Several clinical trials have tested the combination of ATRA and ATO with outstanding results. Furthermore, other trials have explored ATO as a single agent in newly diagnosed patients. ATRA plus ATO has emerged as a promising strategy, even for those with high-risk disease. Future studies will compare ATRA and ATO to conventional ATRA and anthracycline-based chemotherapy.