Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that is ubiquitous in the nervous system and interacts with a myriad of substrates. Its modulation of synaptic plasticity and associated mechanisms of learning and memory as well as neurodegeneration and cognitive disease highlights its importance in the human brain. Cdk5 is active throughout the neuron via its kinase activity, protein-protein interactions, and nuclear associations. It regulates functions thought vital to memory and plasticity, including synaptic vesicle recycling, dendritic spine formation, neurotransmitter receptor density, and neuronal excitability. Although conditional knockout of Cdk5 improves learning and plasticity, the associated deleterious effects of increased excitability cast doubts on the therapeutic efficacy of systemic inhibitors. However, through further work on the regulation of Cdk5 and its effectors, this important molecule promises to aid in elucidating key pathways involved in learning and memory and uncover innovative therapeutic targets to treat neurodegenerative and neuropsychiatric diseases. © 2010 Elsevier Inc.