AbstractCyclin‐dependent kinase 5 (Cdk5) is recognized as an essential molecule in the brain, where it regulates several neuronal activities, including cytoskeletal remodeling and synaptic transmission. While activity of Cdk5 has primarily been associated with neurons, there are now substantial data indicating that the kinase's activity and function are more general. An increasing body of evidence has established Cdk5 kinase activity, the presence of the Cdk5 activators, p35 and p39, and Cdk5 functions in non‐neuronal cells, including myocytes, pancreatic β‐cells, monocytic and neutrophilic leucocytes, glial cells and germ cells. In this review, we present the diverse roles of Cdk5 in several extraneuronal paradigms. The unique properties of each of the different cell types appear to involve distinct means of Cdk5 regulation and function. The potential mechanisms through which Cdk5 regulates extraneuronal cell activities such as exocytosis, gene transcription, wound healing and senescence are discussed. BioEssays 28: 1023–1034, 2006. © 2006 Wiley Periodicals, Inc.