Prurigo nodularis (PN) is a highly pruritic skin condition that is caused by chronic scratching. It occurs in patients with chronic itch and is characterized by multiple hyperkeratotic papules and nodules. The pathogenesis of PN is unclear, but involves a complex interplay of numerous pathways including neurogenic and inflammatory factors. As such, PN is very difficult to treat and patients are often refractory to multiple medications before finding a treatment that is effective. We present a woman with a 20-year history of exuberant prurigo nodularis who failed multiple therapies, including dapsone, azathioprine, mycophenolic acid, prednisone, topical steroids, and phototherapy. She only obtained significant relief of chronic pruritus and lesion flattening with thalidomide 100mg daily. Thalidomide is an antipruritic and anti-inflammatory agent that has shown to be very effective in treating a variety of dermatologic conditions. However, its use today is limited by concerns for its teratogenic and neuropathic side effects. With strict adherence to medication protocols, these adverse effects can be minimized. As such, thalidomide should be considered for patients with refractory dermatologic conditions.