CK2 is a highly conserved, ubiquitously expressed protein serine/threonine kinase present in all eukaryotes. Circumscribed as having a vast array of substrates located in a number of cellular compartments, CK2 has been implicated in critical cellular processes such as proliferation, apoptosis, differentiation, and transformation. Despite advances in elucidating its substrates and involvement in cellular regulation, its precise mode of regulation remains poorly defined. In this respect, there are currently conflicting views as to whether CK2 is constitutively active or modulated in response to specific stimuli. Perhaps an important consideration in resolving these apparent discrepancies is recognition of the existence of many discrete CK2 subpopulations that are distinguished from one another by localization or association with distinct cellular components. The existence of these subpopulations brings to light the possibility of each population being regulated independently rather than the entire cellular CK2 content being regulated globally. Logically, each local population may then be regulated in a distinct manner to carry out its precise function(s). This review will examine those mechanisms including regulated expression and assembly of CK2 subunits, phosphorylation of CK2, and interactions with small molecules or cellular proteins that could contribute to the local regulation of distinct CK2 populations.