Neurons and glial cells are capable of synthesizing bioactive steroids also called neurosteroids which modulate the nervous system activity. Neurosteroids act via autocrine or paracrine mechanisms. Therefore, before neurosteroids can be considered as endogenous modulators of a specific neurophysiologic function, it is compulsory that the process of neurosteroidogenesis occurs in neural pathways controlling this function. Based on pharmacological observations, various studies suggested the involvement of endogenous neurosteroids in the modulation of a variety of neurobiological processes. However, the direct link between these processes and endogenous production of neurosteroids in the nervous system remains unknown. The present review recapitulates a series of results showing the existence of interactions between peripheral nerve injury and neurosteroid biosynthesis in the central nervous system (CNS). In particular, the paper discusses the impact of sciatic nerve ligature on genomic and biochemical components of neurosteroidogenesis in the spinal cord and brainstem areas including the parabrachial, raphe magnus and dorsal raphe nuclei which control nociception. It appears that peripheral nerve injuries evoke changes in the gene expression and biological activity of cytochrome P450side-chain-cleavage, the key enzyme catalyzing the onset of neurosteroidogenesis in the CNS. Owing to neurosteroid involvement in the control of various neurobiological functions, these data suggest that neurosteroidogenesis is an endogenous mechanism activated in the CNS for adaptation of the body to chronic peripheral neuropathies. Therefore, strategies based on selective targeting of neurosteroidogenic pathways may constitute interesting approaches to develop novel therapy against disorders provoked by central and peripheral neuropathies.