Protein kinase CK2 (also termed casein kinase-2 or -II) is a ubiquitous Ser/Thr-specific protein kinase required for viability and for cell cycle progression. CK2 is especially elevated in proliferating tissues, either normal or transformed, and the expression of its catalytic subunit in transgenic mice is causative of lymphomas. CK2 is highly pleiotropic: more than 160 proteins phosphorylated by it at sites specified by multiple acidic residues are known. Despite its heterotetrameric structure generally composed by two catalytic (alpha and/or alpha') and two non catalytic beta-subunits, the regulation of CK2 is still enigmatic. A number of functional features of the beta-subunit which could cooperate to the modulation of CK2 targeting/activity will be discussed.