Phosphorylation of the neuronal cytoskeletal proteins NF-H, NF-M and tau is important for normal axonal development, and is involved in axonal injury and neurodegenerative diseases. In mammalian neurons, one kinase that phosphorylates these axonal cytoskeletal proteins is cyclin-dependent kinase 5 (cdk5). Cdk5 is a member of the family of cyclin-dependent kinases (cdks), whose other family members regulate mitosis. Unlike the other cdks, cdk5 is abundant in differentiated neurons. Embryos of the clawed frog Xenopus laevis have proved useful for studying other cyclin-dependent kinases, neurofilament proteins and tau during development. As a first step in studying the role of cdk5 and its effects on neurofilaments during Xenopus neural development, four cDNA clones were isolated by screening a frog brain cDNA library at lowered stringency with a cDNA probe to rat cdk5. The frog cdk5 clones encoded a protein of 292 amino acids that was 97% identical to rat cdk5. In situ hybridization demonstrated that the Xenopus cdk5 transcript, like that of mammals, was expressed in differentiated post-mitotic neurons. The high degree of sequence homology and shared neuronal expression suggests that the role of cdk5 in neurons is highly conserved between mammals and amphibians. Northern blot analysis indicated that during Xenopus development, cdk5 mRNA was first expressed between the midblastula transition and gastrulation, which both occur long before neuronal differentiation. These stages mark the transition from synchronous to asynchronous cell division and are the earliest stages of zygotic gene expression. This early expression of Xenopus cdk5 mRNA implies a role for cdk5 during embryogenesis that is separate from its role as an axonal cytoskeletal protein kinase. These observations provide the foundation for exploiting X. laevis embryos to study the role of cdk5 both in the early stages of axonal differentiation and also in early embryogenesis.