Acute lymphoblastic leukemia (ALL) is a malignancy with the potential to infiltrate the liver, spleen, lymph nodes and brain. The mechanism for selective homing of ALL cells to preferential sites has long been unclear. Recent reports indicate that the chemokine receptor CXCR4 is found on ALL cells and its ligand is highly expressed at sites associated with ALL-induced organ infiltration. This results in chemotaxis, or directed migration of leukemic cells from the bone marrow via the circulation to preferential sites of extramedullary organ infiltration. Because overexpression of CXCR4 on ALL cells is associated with high extramedullary organ infiltration and shorter disease-free survival, numerous pharmacological agents affecting CXCR4 have currently been investigated. The most promising data are available for histone deacetylase inhibitors (HDAIs), which have been shown to be safe and well tolerated in phase I clinical trials. In vitro, HDAIs extensively down-regulate CXCR4 protein and mRNA levels. As a result, the ability of CXCR4 ligand to induce cellular migration is impaired. Wider recognition of the role of CXCR4 in ALL and manipulation of this important mechanism may lead to novel approaches in the treatment and outcome of this disease.