Childhood acute lymphoblastic leukemia (C-ALL) is the most common pediatric cancer. Although its etiology remains poorly understood, the hypothesis of ALL correlated with a genetic basis was examined through association studies based on candidate genes. Recently, two independent large-scale genome-wide association studies reported that the five single nucleotide polymorphisms (rs7073837; rs10821936; rs10994982; rs7089424; rs10740055) in the gene AT rich interactive domain 5B (ARID5B) at 10q21.2, were associated with the high incidence risk of C-ALL, especially with hyperdiploid lymphoblastic leukemia. Variations in these single nucleotide polymorphisms influence the risk of specific disease subtypes, and also possess race- and sex-differences in leukemia incidence. Further elucidation of the mechanisms through which ARID5B variants are involved in C-ALL not only has a great diagnostic value, but also a guidance for the clinical therapy, ultimately improving the prognosis of disease. Therefore, the related studies of ARID5B with C-ALL were summarized briefly in this review.