Background: Casein kinase II (CK2) is a pro-oncogenic protein, which is emerging as a promising therapeutic target in cancer. Recent studies have revealed an important role for CK2 in tumorigenesis. High levels of CK2 are noted in many malignancies including leukemia. Use of CK2 inhibitors in various malignancies including breast, prostate, and lung cancer are being tested. Although many CK2 inhibitors exist, only a few have emerged as selective inhibitors that are potent and effective. CX-4945 is a selective, orallybioavailable small molecule inhibitor, which has shown encouraging results in pre-clinical models of leukemia.Methods: In this review we will elaborate on the structure and physiological function of the CK2 protein as well as its role in cancer. We will review, in depth, the role of CK2 in leukemia and its mechanisms of tumorigenesis via phosphorylation of the tumor suppressor protein Ikaros. We will discuss both the importance of Ikaros in leukemia suppression and the restoration of Ikaros’ tumor suppressor function after CK2 inhibition by CX-4945 (a CK2-specific inhibitor). Results: CK2 is an oncogene that is overexpressed in hematological malignancies. In high risk Pre-B ALL, CK2 phosphorylates Ikaros tumor suppressor and promotes leukemogenesis. Inhibition of CK2 using CX4945 restores Ikaros function and leads to anti leukemic effects in vitro and in pre-clinical leukemia models. Conclusion: CK2 is an attractive target in treatment of various cancers. Currently only a few specific CK2 inhibitors are available. Preclinical studies using CK2 inhibitor, CX4945 in high risk pediatric leukemias have shown promising results and warrants further testing in other types of leukemia.