Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39 expressed predominantly in neurons. Cdk5 is indispensable for the development of the central nervous system through regulation of neuronal migration. In mature neurons, Cdk5 has been implicated in various signaling transduction pathways, which contribute to functional neuronal activity. It has been widely accepted that aberrant Cdk5 activity induced by the conversion of p35 to p25 plays roles in the pathogenesis of neurodegenerative diseases. Cdk5 also contributes to adaptive changes in the brain related to drug addiction. Moreover, recent studies suggest that Cdk5 plays crucial roles in physiological functions in non-neuronal cells such as glucose-stimulated insulin secretion in pancreatic -cells. The present evidence indicates that Cdk5 might be a potential drug target for the treatment of neurodegenerative diseases, drug abuse and diabetes mellitus. This review focuses on the implication of Cdk5 in the signaling pathways of both neurodegenerative diseases and drug abuse, and the mechanism of Cdk5 involvement in insulin secretion. This review also discusses the possibility of using Cdk5 inhibitors as therapeutic drugs.