Neurofilaments and microtubules are important components of the neuronal cytoskeleton. In axons or dendrites, these filaments are aligned in parallel arrays, and separated from one another by nonrandom distances. This distinctive organization has been attributed to cross bridges formed by NF side arms or microtubule‐associated proteins. We recently proposed a polymer‐brush‐based mechanism for regulating interactions between neurofilaments and between microtubules. In this model, the side arms of neurofilaments and the projection domains of microtubule‐associated proteins are highly unstructured and exert long‐range (...) repulsive forces that are largely entropic in origin; these forces then act to organize the cytoskeleton in axons and dendrites. Here, we review the biochemical, biophysical, genetic and cell biological data for the polymer‐brush and cross‐bridging models. We explore how the data traditionally used to support cross bridging may be reconciled with a polymer‐brush mechanism and compare the implications of recent experimental insights into axonal transport and physiology for each model. BioEssays 26:1017–1025, 2004. © 2004 Wiley Periodicals, Inc. (shrink)