Abstract Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. Despite the remarkable progress over the past decades in curing ALL resulting from the refinement of multiagent chemotherapeutic and radiotherapy regiments, relapsed ALL remains a leading cause of cancer-related deaths in children. The proposed project is based on two clinical observations that cannot be explained by current understanding of leukemia growth and relapse. I hypothesize that chemo-resistant cells are out-competed by other cells in ALL patients with late relapse and in ALL patients who undergo maintenance therapy. In addition, chemo-sensitive cells are out-competed by other ALL cells in patients with early relapse. To test this hypothesis, I will track individual ALL cells in vivo using a single cell tracking technology that was previously developed in our lab. This novel approach will allow the tracing of thousands of individual ALL cells simultaneously in mouse models and help identify the interactions between primary human ALL cells. The goal is to exploit cellular competition and communication to develop novel treatment strategies. These findings will greatly enhance the understanding of ALL relapse and pave the path to new therapeutic strategies that target specific ALL clones.