The primary reason for inadequate analgesic effects of current pharmaceuticals for neuropathic pain is that we do not fully understand the pathophysiological mechanisms that underlie its development. We will discuss the concept that non-neuronal cells residing in the skin (e.g. glia, inflammatory cells) and peripheral mediators (e.g. axon guides) may play a key role in nociceptive signal transduction. This shift in paradigm has opened an exciting field of studies with regard to pain mechanisms. We will present potential implications on clinical practice. Data from preclinical and clinical studies will be discussed critically focusing on Schwann cells and other glia cells, keratinocytes, fibroblasts, mechanoreceptors, ion channels, and axon guidance mechanisms. Lastly, we will present new data on changes in cutaneous sensory and sympathetic vaso- and sudomotor innervation in peripheral and central neuropathic pain conditions. Experimentally- and pathology-induced changes using 8% capsaicin will be related to the clinical (pain) phenotype, and novel insights into potential therapeutic targets showcased.