Background. Prurigo nodularis is a chronic reaction pattern associated with severe pruritus that markedly affects the quality of life in patients. Pathogenesis. The pathogenesis of prurigo nodularis is not completely clear. Patients have an increased number of substance P and calcitonin gene-related peptide positive nerves in the dermis. Eosinophils and mast cells are in close vicinity to peripheral nerves and increased in numbers in the inflammatory infiltrate in prurigo nodularis. Nerve growth factor (NGF) is increased in lesional skin of patients and can be released by mast cells and eosinophils. In addition, NGF modulates the functional activity of mast cells and eosinophils. Recently, higher levels of the novel pruritic cytokine IL-31 were found in the skin of patients with prurigo nodularis than other pruritic skin diseases. Conclusion. The pathogenesis of prurigo nodularis seems to be regulated by immunological and neuronal plasticity which will be highlighted in the current article.