There are a number of special considerations regarding endoscopic repair of cerebrospinal fluid (CSF) leaks and encephaloceles occurring in the sphenoid sinus. The sphenoid sinus is formed by the anterior and middle cranial fossae, is in close proximity to the internal carotid artery and optic nerve, and may have extreme lateral pneumatization that limits accessibility via normal endoscopic routes. Although CSF leaks and encephaloceles can occur anywhere within the sphenoid sinus, they are generally divided into a medial, perisellar type and a lateral, sphenoid recess type. The diverse etiologies of sphenoid sinus CSF leaks make it essential to have a thorough understanding of the underlying pathophysiology, and treatment principles and treatment options to achieve excellent outcomes. The specific surgical approach for a sphenoid sinus skull base defect is dependent on the exact site of the defect within the sphenoid sinus. Once an appropriate endoscopic approach with wide local exposure is obtained, reconstruction of the skull base is dependent on the etiology of the leak and other factors, including the underlying intracranial pressure. This article will highlight the surgical techniques and perioperative care relevant to sphenoid CSF leaks and encephaloceles.