Initial attempts at transcranial approaches to the pituitary gland in the late 1800s and early 1900s resulted in a mortality rate that was generally considered prohibitive. Schloffer suggested the use of a transsphenoidal route as a safer, alternative approach to the sella turcica. He reported the first successful removal of a pituitary tumor via the transsphenoidal approach in 1906. His procedure underwent a number of modifications by interested surgeons, the culmination of which was A. E. Halstead's description in 1910 of a sublabial gingival incision for the initial stage of exposure. From 1910 to 1925, Cushing, combining a number of suggestions made by previous authors, refined the transsphenoidal approach and used it to operate on 231 pituitary tumors, with a mortality rate of 5.6%. As he developed increasing expertise with transcranial surgery, however, Cushing reduced his mortality rate to 4.5%. With the transcranial approach, he was able to verify suprasellar tumors and achieve better decompression of the optic apparatus, resulting in better recovery of vision and a lower recurrence rate. As a result he and most other neurosurgeons at the time abandoned the transnasal in favor of the transcranial approaches. Norman Dott, a visiting scholar who studied with Cushing in 1923, returned to Edinburgh, Scotland, and continued to use the transsphenoidal procedure while others pursued transcranial approaches. Dott introduced the procedure to Gerard Guiot, who published excellent results with the transsphenoidal approach and revived the interest of many physicians throughout Europe in the early 1960s. Jules Hardy, who used intraoperative fluoroscopy while learning the transsphenoidal approach from Guiot, then introduced the operating microscope to further refine the procedure; he thereby significantly improved its efficacy and decreased surgical morbidity. With the development of antibiotic drugs and modern microinstrumentation, the transsphenoidal approach became the preferred route for the removal of lesions that were confined to the sella turcica. The evolution of the transsphenoidal approaches and their current applications and modifications are discussed.