The findings that cyclin-dependent protein kinase 5 (Cdk5), and its neuronal activators p35, are involved in the route by which amyloid beta peptide Aß triggers brain neuronal death in neurodegenerative disorders such as Alzheimer disease have generated a marked interest among cell biologists and neuroscientists. Cdk5 is a Ser-Thr protein kinase with postmitotic activity that phosphorylates KSP protein motifs on MAP1b, KSPXK on tau or KSPXX on neurofilament proteins. Substrates for this enzyme also include the actin-binding protein caldesmon and proteins of the synaptic vesicles. Cdk5 is one of the main kinases phosphorylating the microtubule associated protein tau in neuronal cells, a fact reflected in its designation as Tau protein kinase II (TPKII). This kinase was originally identified and cloned from HeLa cells and exhibited biochemical similarities to mitotic regulator cdc2. However, this is a unique member of the cyclin-dependent kinase family not directly involved in progression of proliferating cells through the cell cycle. Cdk5 is distributed in several tissues and cell lines, even though a preferential distribution and activity in differentiating brain neurons has been found. This enzyme is active primarily in neuronal tissue, while a minor level of activity has been detected in muscle cells. Recent evidence indicates that the Cdk5/p35 system participates in normal axonal growth and the extension of neuritic processes in neurons. Furthermore, Cdk5/p35 kinase is involved in neuronal migration and differentiation during development of the nervous system. In the mature brain, it might play a role in maintaining neuronal plastic potential in brain regions such as the limbic system. Cdk5 is important for the fine regulations of postranslational events that trigger subcellular changes in the cytoskeleton organization. The critical Cdk5 roles in phosphorylating tau and MAP1b, two cytoskeletal proteins necessary for polarity determination in neurons, and its involvement in neuronal development, indicate that sensitive mechanisms operate in regulating its cellular activity. The present series of reviews attempts to analyze in an integrative fashion relevant data on Cdk5 involvement in normally regulated developmental processes of the brain, as well as the biochemical and cellular changes affecting this enzyme, and therefore tau phosphorylations in degenerating neurons. In the context of neurodegeneration and Alzheimer’s disease, many conferences and review articles focus on relevant aspects of amyloid deposition in brain, or tau pathology. Thus, an approach linking molecular event during brain and particularly neuronal development with such neurodegenerative disorders appears to be of the utmost importance at the present stage of this research. Considering the cellular importance of this unique protein kinase and its loss of regulation in degenerating neuronal cells, an analysis of structural–functional aspects of this enzyme, and its interaction patterns with neuronal proteins within the perspective of neuronal development, may shed light on the study of such neurodegenerative disorders. The article by Paglini and Cáceres reviews some of the experimental evidence supporting a central role for Cdk5/p35 kinase in neuronal migration and formation of neuronal processes. In addition to this functional analysis in a developmental context, the review by Pant focuses primarily on Cdk5 roles in processing and regulating neurofilament protein assemblies, as well as on the nature of phosphorylations of these proteins and their transport within neurons. Structural aspects of Cdk5 are analyzed here in the review by Maccioni and coworkers. This article also focuses on the alteration of normal molecular signaling controlling Cdk5 function in developing neurons, based on recent studies indicating that deregulation of Cdk5 activity is determinant in the process leading to neuronal death in degenerating neurons. These findings have strong implications in the pathology of Alzheimer’s disease. Stabilization of the Cdk5/p35 complex appears to be a major factor that promotes a constitutive activation of Cdk5 in the pathway leading to neuronal death in neurodegenerative disorders, a process which seems to depend on Cdk5 phosphorylation. This over-activation of Cdk5 could lead to critical tau hyperphosphorylations resulting in dramatic changes in tau’s behavior, and a significant decrease in its interaction with neuronal microtubules and neurofilaments. Thus, the possible molecular mechanisms underlying Cdk5 deregulation and tau self-aggregation constitute an important part in this analysis. We expect that this review series will contribute to integrate the information at the present stage of Cdk5 research and provide insights into the biochemical and cellular aspects surrounding the roles of Cdk5 in the central nervous system and in neuronal pathology.