This case is about a 35-week neonate diagnosed with harlequin ichthyosis. The neonate was managed by a multidisciplinary team composed of specialists from neonatology, genetics, dermatology, plastic surgery, ophthalmology, rehabilitation medicine, and anesthesiology.Harlequin ichthyosis is characterized by defective keratinization and desquamation of the epidermis which is very painful. Pain management in the neonate entails a proper balance between pain relief and avoidance of serious adverse effects which is a major challenge for caregivers.