Arsenic trioxide (As 2O 3) induces both the differentiation and apoptosis of acute promyelocytic leukemia cells in a concentration dependent manner. We assessed the effects of As 2O 3 in CADO-ES Ewing’s sarcoma (ES), JK-GMS peripheral primitive neuroectodermal tumor (PNET), and SH-SY5Y neuroblastoma cells, as they share common histogenetic backgrounds. As 2O 3 at low concentrations (0.1–1 μM) induced SH-SY5Y differentiation, and whereas PNET cells acquired a slightly differentiated phenotype, change was minimal in ES cells. Extracellular signal-regulated kinase 2 (ERK2) was activated at low As 2O 3 concentrations, and PD98059, an inhibitor of MEK-1, blocked SH-SY5Y cell differentiation by As 2O 3. High concentrations (2–10 μM) of As 2O 3 induced the apoptosis in all three cell lines, and this was accompanied by the activation of c- jun N-terminal kinase. The generation of H 2O 2 and activation of caspase 3 were identified as critical components of As 2O 3-induced apoptosis in all of the above cell lines. Fibroblast growth factor 2 enhanced As 2O 3-induced apoptosis in JK-GMS cells. The overall effects of As 2O 3 strongly suggest that it has therapeutic potential for the treatment of ES/PNET.