Leukemia is the most common childhood malignancy.Pediatric acute leukemia (AL) mainly includes acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) subtypes, which occupy approximately 76% and 20% of childhood leukemia respectively.Although the long-term disease-free survival (DFS) and overall survival (OS) rate of pediatric leukemia has been improved recently, there is still about 25% relapse rate.The risk stratification is pivotal for pediatric leukemia prognosis and its personalized therapy to reduce relapse.Some factors are important and widely used for childhood AL risk stratification.Among these factors, leukemia stem cells (LSCs) are critical to identify residual immature blast cells for minimal residual disease monitoring, as well as the independent prognostic factors for leukemia.Based on our previous results of the tumorigenic role of β-arrestins, the multifunctional scaffold protein mediating many intracellular signaling networks was found to be involved in many tumors.However, little is known in leukemia.Here aberrant β-arrestin1 expression and regulation in pediatric leukemia, especially in the LSCs, results from different investigations, functionality and the relationship between β-arrestin1, LSCs and DNA methylation will be presented and discussed.