Sphenoid isolated lesions are rare; they occur in 2% to 3% out of all paranasal sinus lesions. Diagnosis is based on the endoscopic examination and computed tomography scan or magnetic resonance imaging of the maxillofacial area. In this study, we present patients with sphenoid mucocele in the Maxillo-facial Surgery Department, University of Rome La Sapienza, treated with the endoscopic technique. Moreover, a literature review is performed, dealing with the evolution of approaches to the sphenoid sinus. From January 2001 to January 2007, we treated 75 patients affected by paranasal sinus mucocele. Out of this number, 8 patients (11%) presented an isolated localization in the sphenoid sinus. These patients were divided as follows: 5 involved the right sphenoid sinus and 3 involved the left sphenoid sinus. Isolated sphenoid sinus disease is a rare entity that can result in serious sequelae if diagnosis and treatment are inappropriately delayed. In our study, we highlighted how the endoscopic approach allows the removal of even large mucocele with the use of 45-degree angle optic and if it is possible to control and remove lateral walls of the sphenoid sinus. In our experience, we shifted from a traditional approach to the endoscopic approach. At the present time, the endoscopic approach represents the gold standard for sphenoid sinus mucocele treatment because it allows the best view of the sphenoid sinus and grants a better restoring of respiratory function and a higher compliance from the patient.