Cyclin-dependent kinase 5 (Cdk5) is a multifaceted serine/threonine kinase protein with important roles in the nervous system. Two related proteins, p35 and p39, activate Cdk5 upon direct binding. Over the past decade, Cdk5 activity has been demonstrated to regulate many events during brain development, including neuronal migration as well as axon and dendrite development. Recent evidence also suggests a pivotal role for Cdk5 in synaptic plasticity, behavior, and cognition. Dysfunction of Cdk5 has been implicated in a number of neurological disorders and neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Niemann-Pick type C disease, and ischemia. Hyperactivation of Cdk5 due to the conversion of p35 to p25 by the calcium-dependent protease calpain during neurotoxicity also contributes to the pathological state. This review surveys recent literature surrounding Cdk5 in synaptic plasticity and homeostasis, with particular emphasis on Cdk5 kinase activity under neurodegenerative conditions.