Protein kinase CK2 is a serine/threonine kinase with a multitude of protein substrates. The enzyme is ubiquitously expressed in mammalian cells, where it functions in a variety of cellular processes, including cell cycle progression, apoptosis, transcription, and viral infection. While the importance of CK2 in the mammalian life cycle is undisputed, the regulatory mechanisms coordinating its numerous functions remain elusive. In this review, we focus on the various roles of CK2 in the mammalian cell, with particular attention on its functions through the stages of the cell cycle and during the decision to undergo cell death. We highlight how these roles are controlled in part through direct transcriptional regulation by CK2, and how the constitutive activity of CK2 can be hijacked in the case of viral infection. Finally, we discuss possible ways in which these functions are integrated to allow the cell to respond appropriately in the presence of multiple signals.