Cdk5, a cyclin-dependent kinase family member, is a global orchestrator of neuronal cytoskeletal dynamics. During embryogenesis, Cdk5 is indispensable for brain development. In adults, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation, drug addiction, pain signaling, and long-term behavior changes through long-term potentiation and long-term depression, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity becomes deregulated in various brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, attention-deficit hyperactivity disorder, epilepsy, schizophrenia, and ischemic stroke; these all result in profound remodeling of the neuronal cytoskeleton. This Commentary specifically focuses on the pleiotropic contribution of Cdk5 in regulating neuronal microtubule remodeling. Because the vast majority of the physiological substrates of Cdk5 are associated with the neuronal cytoskeleton, our emphasis is on the Cdk5 substrates, such as CRMP2, stathmin, drebrin, dixdc1, axin, MAP2, MAP1B, doublecortin, kinesin-5, and tau, that have allowed to unravel the molecular mechanisms through which Cdk5 exerts its divergent roles in regulating neuronal microtubule dynamics, both in healthy and disease states.