Neurons in the central nervous system (CNS) are extensively interconnected, and consequently almost half of the human brain is occupied by wiring in the form of the myelinated axons. Dysfunction and degeneration of these axons can result in profound and permanent disability. Axons are much more complex than simple wires, however. Signal propagation relies on elaborate ultrastructural specializations at the nodes of Ranvier, which are demarcated by gaps between myelin sheaths. As living extensions of neurons, axons also require constant replenishment of metabolites and organelles such as energy-generating mitochondria. Studies of pathogenesis of myelinated axons are often constrained by microscopic complexity that requires nanometer-scale resolution over substantial three-dimensional distances.