Arsenic compounds exert important biological effects and arsenic trioxide has been approved by the Food and Drug Administration (FDA) for the treatment of patients with acute promyelocytic leukemia (APL). Much of arsenic's actions in cells reflect its ability to bind thiol groups in cellular proteins or to affect the production of reactive oxygen species (ROS), leading to the engagement and regulation of several cellular signaling pathways. Arsenic has been also shown to degrade abnormal fusion proteins found in myeloid leukemias. It has also been shown to effect NFκB, MAPK, mTOR and Hedgehog pathways which can modulate the viability of cancer cells. Many clinical trials have been performed to examine the clinical efficacy of arsenic trioxide alone or in combination with other agents in the treatment of various hematological malignancies. The continuous advances in basic and translational research and the better understanding of the mechanisms of action of arsenic should lead to more effective combinations with other agents that could result in better clinical outcomes.