Cyclin-dependent kinase 5 (Cdk5) is a multi-faced kinase implicated in both development and disease of the mammalian central nervous system. These different faces of Cdk5 are preferentially regulated by the activation of Cdk5 by its different binding partners. The precise molecular and cellular mechanisms governing the role of Cdk5 in brain development and disease are unclear. Emerging evidence is now unraveling how Cdk5 normally orchestrates new signaling pathways that dictate the proper maturation and maintenance of the central nervous system. Under pathological conditions, however, Cdk5 activity goes awry and the malevolent face of Cdk5 surfaces. Recently developed animal models that display this deregulated Cdk5 activity reveal the intimate involvement of Cdk5 in tau pathology and neuronal cell death, and underscore the importance of phosphorylation in the progression of neurodegenerative diseases.