Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy, accounting for approximately 80 % of leukemia in the pediatric group, and its etiology is unknown. This neoplasia is characterized by male predominance, high-risk features and poor outcome, mainly in recurrence patients and adults. In recent years, advances in the success of childhood ALL treatment were verified, and the rate of cure is over 80 % of individuals. However, there is a considerable scope for improving therapeutic outcome in this neoplasia. Improvements in ALL therapy might readily be achieved by developing additional biomarkers that can predict and refine prognosis in patients with ALL. In normal hematopoietic cells, cytokines provide the stimulus for proliferation, survival, self-renewal, differentiation and functional activation. Abnormalities of cytokines are characteristic in all forms of leukemia, including ALL. The stromal cell-derived factor-1 (SDF-1 or CXCL12) is a member of the CXC chemokine family that binds to CXC chemokine receptor 4 (CXCR4). The CXCL12/CXCR4 axis appears to play a role in dissemination of solid tumors and hematopoietic diseases. Understanding the mechanisms by which ALL cells are disseminated will provide additional information to expand therapeutic approach. Therefore, this review summarizes information relating to ALL cell biology, focusing specifically in a cytokine receptor important axis, CXCL12/CXCR4, that may have implications for novel treatment strategies to improve life expectancy of patients with this neoplasia.