The wealth of biochemical, molecular, genetic, genomic, and bioinformatic resources available in S. cerevisiae make it an excellent system to explore the global role of CK2 in a model organism. Traditional biochemical and genetic studies have revealed that CK2 is required for cell viability, cell cycle progression, cell polarity, ion homeostasis, and other functions, and have identified a number of potential physiological substrates of the enzyme. Data mining of available bioinformatic resources indicates that (1) there are likely to be hundreds of CK2 targets in this organism, (2) the majority of predicted CK2 substrates are involved in various aspects of global gene expression, (3) CK2 is present in several nuclear protein complexes predicted to have a role in chromatin structure and remodeling, transcription, or RNA metabolism, and (4) CK2 is localized predominantly in the nucleus. These bioinformatic results suggest that the observed phenotypic consequences of CK2 depletion may lie downstream of primary defects in chromatin organization and/or global gene expression. Further progress in defining the physiological role of CK2 will almost certainly require a better understanding of the mechanism of regulation of the enzyme. Beginning with the crystal structure of the human CK2 holoenzyme, we present a molecular model of filamentous CK2 that is consistent with earlier proposals that filamentous CK2 represents an inactive form of the enzyme. The potential role of filamentous CK2 in regulation in vivo is discussed.