Characterized by the clinical presentation of individual to multiple symmetrically distributed, hyperkeratotic, and intensely itchy papules and nodules, prurigo nodularis (PN) is a rare disease that emerges in patients with chronic pruritus due to continuous scratching over a long period of time. The itching and scratching of the lesions contribute to the vicious cycle that makes this disease difficult to treat, thus reducing the quality of life of affected patients. The pathogenesis of PN is ambiguous, although immunoneuronal crosstalk is implicated. Its etiology was found to be heterogenous. It can emerge as the symptom of various dermatological, neurological, psychiatric, and systemic diseases. There is currently no approved therapy for PN. However, contemporary therapies consist of calcineurin inhibitors, capsaicin, topical steroids, UV therapy, and a systemic application of antihistamines, anticonvulsants, μ-opioid receptor antagonists, and immunosuppressants. Multimodal therapy should be utilized in order to achieve optimal results, including topical and systemic symptomatic therapies.