Neuronal Cdc2-like kinase, Nclk, is a heterodimer of a Cdk5 catalytic subunit and a 25 kDa regulatory subunit derived proteolytically from a neuron- and central nervous system-specific 35 kDa protein. The regulatory subunit is mandatory for kinase activity, hence it is designated the neuronal Cdk5 activator, p25/p35nck5a. Nclk has been suggested to play a regulatory role in neuro-cytoskeleton dynamics and in neuronal differentiation. In addition to the activation by Nck5a, Cdk5 is regulated by other mechanisms including additional activator proteins and inhibition by phosphorylation of specific amino acid residues. While Nclk shares common catalytic and regulatory properties with other members of the cdc2-like kinase family, it also displays unique characteristics that may be important for its neuronal functions.