Signal transduction in a broad sense refers to intracellular, molecular changes triggered by cues outside the cell in order to bring about behavioral responses such as migration, differentiation, secretion, or death. Until recently, the best-studied end targets of signal transduction pathways were transcriptional regulators that contribute to changes in gene expression. However, it is clear that many pathways can act through mechanisms other than, or in addition to, transcription control. The three major cytoskeletal systems, microtubules, intermediate filaments, and filamentous actin, are targets for this kind of regulation. Acute changes in cytoskeletal organization are particularly important during embryonic development, when many cells are motile and undergo dramatic changes in shape. Cytoskeletal dynamics are also important in motile cells in adult systems and, in a more limited way, in cells that carry out rapid, regulated secretion. Even changes in synaptic efficacy may involve structural modifications requiring changes in the neuroskeleton. Cytoskeletal reorganization can itself be viewed as signal transduction, producing changes in molecular trafficking and interactions. This review considers evidence that cyclin-dependent kinase 5 is a modulator of neuroskeletal dynamics.