Peripheral nerve regeneration (PNR) remains among the greatest challenges in Tissue Engineering and Regenerative Medicine (TERM). Peripheral nerve injuries (PNIs) are very common and costly and have confounded professionals in this field, from neuroscientists to neurologists, plastic surgeons, and the scientific community. Even though PNIs are capable of some degree of regeneration, poor recovery is seen even when the best microsurgical technique is used. Despite all the efforts, full functional recovery is still rare. These injuries are known to be very debilitating for the patient, due to the loss of motor and sensory functions. However, the inadequate results attained with the “gold standard” autograft procedure still encourage a dynamic and energetic research around the world for establishing good performing tissue engineered alternative grafts, the nerve guidance conduits (NGCs). Therefore, since there is no optimal solution for tackling this problem up to this day, the evolution in the field is constant, with innovative designs of advanced NGCs being constantly described. Herein, we aim to review the basic concepts related to peripheral nerve anatomy and overview the scientific evidences related to peripheral nerve injury and intrinsic repair mechanisms. Furthermore, the basic notions of the NGCs functionality must be well-known. A NGCs should act as a physical barrier from the external environment, concomitantly acting as physical guidance for the regenerative axons across the gap. In more detail, a NGC should retain the naturally released nerve growth factors secreted by the damaged nerve stumps (which can be incorporated with multiple strategies), as well as reducing the invasion of scar tissue-forming fibroblasts to the injury site. Based on the neurobiological knowledge related to the events that succeed after a nerve injury, neuronal survival is subjected to the existence of an ideal environment of growth factors, cytokines and extracellular matrix (ECM) factors. Hence, it is known that a multifunctional NGC fabricated through combinatorial approaches is needed to improve the functional and clinical outcomes after nerve injuries. This field is being increasingly seen as an interdisciplinary and integrated field where multiple and varied expertise is required. The present work reviews the current strategies dealing with several features that can be used to improve PNR, ranging from simple use of hollow NGCs to intraluminal fillers, or more advanced strategies comprising the molecular and gene therapies, cell-based therapies and nanotechnology.