Protein kinase CK2 targets a vast array of substrates located in a number of cellular compartments, making the challenge of discriminating among these substrates a daunting task. However, as a signaling protein, CK2 could be targeted to different cellular compartments in response to various stress stimuli such as heat shock, UV irradiation, hypoxia, DNA damage and viral infections. This review will be focused on the evidence that the dynamic association of CK2 subunits and the substrate-dependent subcellular targeting of the enzyme are a likely point of regulation in response to a variety of signaling events. We propose that in addition to enzymatic substrate recognition, regulated CK2 localization to specific compartments should help to provide the exquisite specificity required for robust signal transduction.