Abstract: Peripheral nerves coordinate signal transduction from the periphery to the central nervous system for processing and transmission back as required for normal mammalian function. Peripheral nerves and nerve roots are structurally divided into three compartments: the outermost epineurium, inner perineurium that surrounds nerve fascicles and the innermost endoneurium (Mizisin and Weerasuriya, 2011). As with all organs, peripheral nerve vascularization occurs during development and is maintained in health. Adaptations are expected dependent on tissue-specific functions and physiologic state. The peripheral nerve internal microenvironment is tightly controlled to facilitate coordinated and regulated axonal transmission. Peripheral nerves and nerve roots are perfused by extrinsic blood vessels called the vasa nervorum. These macrovessels penetrate the outer epineurium to give rise to epineurial arteries and arterioles and receive blood from epineurial venules and veins. Macrovessels subsequently transverse the inner perineurium, formed by multiple concentric layers of specialized epithelioid myofibroblasts, to perfuse the innermost endoneurium, in which reside myelinated and unmyelinated axons in a loose array of collagen fibers. Non-fenestrated tight junction-forming capillary-like microvessels exist within the endoneurium which are in direct contact with circulating blood. Thus, these microvessels are considered to form the blood-nerve barrier (BNB) (Ubogu, 2020). Tight junction-forming perineurial myofibroblasts provide a critical interface between the endoneurial and epineurial interstitial fluid compartments that further regulate the endoneurial microenvironment; however, these cells are not in direct contact with circulating blood. Peripheral neuropathies affect over 100 million people worldwide, and a common consequence of peripheral nerve disease is chronic pain, which may affect as many as 1% of individuals during their lifetimes. Understanding peripheral nerve molecular and biophysical microvascular adaptations and BNB function during development and in normal physiological states, as well as in diseases, including peripheral nerve injury, provides an avenue to understand how peripheral nerve regeneration and homeostatic restoration may occur. These processes could be harnessed for therapeutic development in peripheral neuropathies and chronic neuropathic pain to support neural regeneration and restore normal biological function.