On axonal surfaces that flank the node of Ranvier and in overlying glial paranodal loops, proteins are arranged within circumscribed microdomains that defy explanation by conventional biosynthetic mechanisms. We postulate that the constraint of proteins to these loci is accomplished in part by discriminative membrane-embedded molecular sieves and diffusion barriers, which serve to organize and redistribute proteins after delivery by vesicular transport to neural cell plasma membranes. One sieve likely comprises a moveable, macromolecular scaffold of axonal and glial cell-derived transmembrane adhesion molecules and their associated cytoplasmic binding partners, located at the ends of each elongating myelin internode; this sieve contributes to restricting the sodium channel complexes to the node. We also anticipate the existence of a passive paranodal diffusion barrier at the myelin/noncompact membrane border, which prohibits protein diffusion out of contiguous paranodal membranes.