The blood-nerve barrier (BNB) defines the physiological space within which the axons, Schwann cells, and other associated cells of a peripheral nerve function. The BNB consists of the endoneurial microvessels within the nerve fascicle and the investing perineurium. The restricted permeability of these two barriers protects the endoneurial microenvironment from drastic concentration changes in the vascular and other extracellular spaces. It is postulated that endoneurial homeostatic mechanisms regulate the milieu intérieur of peripheral axons and associated Schwann cells. These mechanisms are discussed in relation to nerve development, Wallerian degeneration and nerve regeneration, and lead neuropathy. Finally, the putative factors responsible for the cellular and molecular control of BNB permeability are discussed. Given the dynamic nature of the regulation of the permeability of the perineurium and endoneurial capillaries, it is suggested that the term blood-nerve interface (BNI) better reflects the functional significance of these structures in the maintenance of homeostasis within the endoneurial microenvironment.