Introduction The transsphenoidal approach was initially developed in neurosurgical practice as an operative approach to the pituitary gland. The introduction of the operating endoscope has improved the versatility of the transsphenoidal approach, broadening the spectrum of lesions that can be treated effectively with this operative strategy. Methods We performed a retrospective review of all patients who underwent transnasal, transsphenoidal operations at Brigham and Women's Hospital from April 2008 to February 2015 and categorized each case by pathologic diagnosis. Results A total of 792 transnasal, transsphenoidal operations (512 endoscopic) were performed by 9 neurosurgeons for 33 pathologies over a 7-year period. Pituitary adenomas (535, 67.55%) were the most common impetus for a transsphenoidal operation. Others included Rathke cleft cysts (86, 10.86%), craniopharyngiomas (25, 3.16%), lympocytic hypophysitis/pituitary inflammation (21, 2.65%), arachnoid cysts (8, 1.01%), spindle cell oncocytoma (4, 0.51%), colloid cysts (4, 0.51%), and pituicytoma (2, 0.25%). Pituitary hyperplasia was treated in 9 cases (1.14%) and pituitary apoplexy in 7 (0.88%). Nineteen operations were undertaken for postoperative repairs (2.40%) and 3 for abscesses (0.38%). Other diseases treated transsphenoidally included chordomas (12, 1.52%), metastases (9, 1.14%), meningiomas (5, 0.63%), clival lesions (4, 0.51%), germinomas (3, 0.38%), granulomas (2, 0.25%), dermoid tumors (2, 0.25%), and 1 (0.13%) each of esthesioneuroblastoma, granular cell tumor, Wegener granulomatosis, olfactory neuroblastoma, glioneuronal tumor, chondromyxoid fibroma, epidermoid, meningoencephalocele, aneurysm, neuroendocrine carcinoma, chondrosarcoma, and lymphoma. Conclusions Although initially devised in neurosurgical practice for tumors of the pituitary gland, developments in technology now make the transsphenoidal approach an effective operative strategy for a wide range of anterior skull base lesions.