Cyclin-dependent kinase, Cdk5, is an atypical but essential member of the Cdk family of proline-directed serine/threonine kinases with no evident role in cell cycle progression. Cdk5 is present in post-mitotic and terminally differentiated neuronal/glial cells and is also known to arrest cell cycle. Also atypical is the activation of Cdk5 by binding of a non-cyclin activator protein, namely, the Cdk5 regulatory proteins Cdk5R1 (p35), truncated Cdk5R1 (p25), or Cdk5R2 (p39). Despite its ubiquitous presence in all cells and tissues, Cdk5 is often referred to as a neuron-specific kinase largely due to the abundant presence of the activator proteins in neuronal cells. Recently, this concept of a canonical neuronal function of Cdk5 has been extended, if not challenged, by the observation of p35 and p39 expression, as well as Cdk5 activity, in multiple non-neuronal cells. Extraneuronal Cdk5 regulates critical biological processes including transcript-selective translation control for regulation of macrophage gene expression, glucose-inducible insulin secretion, hematopoietic cell differentiation, vascular angiogenesis, cell migration, senescence, and wound-healing, among others. Recent advances in the extraneuronal functions of Cdk5 are reviewed and discussed here in the context of their physiological activities and pathophysiological implications with some speculative comments on the endogenous control mechanisms that might "turn on" Cdk5 activity. The potential importance of targeted inhibition of Cdk5 as therapeutic agents against glucotoxicity, diabetes, cardiovascular diseases, and cancer is also discussed.