CASK is a member of the membrane-associated guanylate kinase family. In mammals it is an essential protein, as CASK knockout mice die after birth and its deletion in humans has developmental consequences. CASK plays a role in the transcription of genes required for forebrain development, and in the nervous systems of Drosophila and C. elegans, it participates in receptor localization at the plasma membrane. This role in organizing supramolecular protein complexes to appropriate subcellular regions is shared in mammals and is regulated by phosphorylation. CASK is a kinase and regulator of cell proliferation and adhesion, which adds to an expanding list of roles. In this study we report for the first time that CASK is degraded in a characteristic fashion in mammalian cells. We found that CASK is a long-lived protein despite the fact that it contains three putative PEST sequences. Finally, we provide detailed evidence that CASK degradation is mediated through a ubiquitin-proteasome pathway and this is phosphorylation-dependent. Together, these results provide evidence that post-translational modifications to CASK are major regulatory steps leading to its proteasomal degradation. This regulation not only has important implications on how CASK participates in its many disparate roles, but highlights how altering this regulation may contribute to the pathogenesis of human disease.