Forty‐five patients with isolated sphenoid sinus lesions were seen at the Mayo Clinic between 1935 and 1972. The types of lesions that these patients had included inflammatory lesions (chronic sphenoid sinusitis and mucopyoceles), tumors, fibrous dysplasia, rhinoliths, and sphenoid polyp. A review of the anatomy and important structures contiguous to the sphenoid sinus reflected the range and progression of clinical symptoms. Complications included pain or headache, visual disturbance including blurred vision, diplopia, exophthalmos, blindness, meningitis, and even death. The most frequent presenting symptoms were headache, retro‐orbital pain, nasal congestion, and visual disturbance, especially diplopia. Some time during the course of the illness, 40. percent of the patients developed visual involvement. Diagnosis was made with the aid of the patient's history and physical examination, whereas the laboratory studies usually were negative, and roentgenographic findings ranged from thickening to fluid levels and bony erosion or frank destruction of the floor of the sella. Fifteen percent of the roentgenograms were false‐negatives, all of which were noted in patients with inflammatory lesions. The differential diagnosis includes pituitary lesions, although the clinical features, the bitemporal hemianopsia, and hypopituitary function, which are characteristic of pituitary tumors, are absent in isolated sphenoid sinus lesions. Mild degrees of panhypopituitarism may exist with inflammatory lesions of the sphenoid sinus. Definitive diagnosis and therapy are usually effected by transnasal exploration of the sphenoid sinus.