Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase. Despite the high degree of homology between CDK5 and other conventional cyclin-dependent kinases (CDKs) that are important for mitotic cell division, CDK5 usually is not directly involved in cell cycle regulation. Instead, it is abundantly expressed in post-mitotic cells such as neurons and is necessary for neural differentiation. It is now well accepted that CDK5 plays important roles in multiple cellular events, such as cytoskeletal dynamics, signaling cascades, gene expression, and cell survival. As a result, CDK5 dysregulation has been implicated in various diseases, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD).