Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine (ser)/threonine (Thr) kinase that has been demonstrated to be one of the most functionally diverse kinases within neurons. Cdk5 is regulated via binding with its neuron-specific regulatory subunits, p35 or p39. Cdk5-p35 activity is critical for a variety of developmental and cellular processes in the brain, including neuron migration, memory formation, microtubule regulation, and cell cycle suppression. Aberrant activation of Cdk5 via the truncated p35 byproduct, p25, is implicated in the pathogenesis of several neurodegenerative diseases. The present review highlights the importance of Cdk5 activity and function in the brain and demonstrates how deregulation of Cdk5 can contribute to the development of neurodegenerative conditions such as Alzheimer's and Parkinson's disease. Additionally, we cover past drug discovery attempts at inhibiting Cdk5-p25 activity and discuss which types of targeting strategies may prove to be the most successful moving forward.