Cyclin dependent kinase-5 (Cdk5), a key regulator of cell cycle progression, was originally isolated on the basis of its structural homology to Cdc2, a wellcharacterized regulator of cell cycle progression. Although Cdk5 is expressed at the highest level in the brain of adult mice, intermediate levels in testis and low or undetectable levels in all other tissues, brain is the only tissue from which Cdk5 can be isolated as an active kinase. These findings may be explained by the cloning and characterization of a Cdk5 regulatory subunit, designated p35. p35 displays a neuronal cell-specific pattern of expression, physically associates with Cdk5 and activates Cdk5 enzymatic activity. p35 is also expressed in many tissues in a truncated form, designated p25.