While the endonasal approach to the skull base continues to advance, this paper invokes its long history. The centuries of medieval neuroanatomy and early neurosurgery enabled the conception of the first transfacial approaches in the late 1800s; Henry Schloffer performed the first transsphenoidal surgery in 1907. Although the procedure was initially met with much interest, Harvey Cushing eventually led the field of neurosurgery to abandon the transsphenoidal approach in the 1920s. The following three generations of neurosurgeons contained several key figures including Norman Dott, Gerard Guiot, and Jules Hardy who were steadfast in preserving the technique as well as in addressing its shortcomings. The endoscopic approach developed simultaneously, and advances in magnifying and fiberoptics further resolved limitations previously inherent to the transsphenoidal approach. At last, in the 1960s, the transsphenoidal approach entered its renaissance. Today, the momentum of its development persists in the endoscopic endonasal approach, which has recently expanded the indications for transsphenoidal surgery across the skull base, far beyond its original jurisdiction of the sella. Continued progress must not take for granted the rich history of the transsphenoidal approach, which was developed over centuries by surgeons around the world. The authors present the evolution of modern endonasal surgery as a dynamic interplay between technology, medicine, and surgery over the past 100 years. Progress can be attributed to courageous surgeons who affirmed their contemporary practices despite gaps in technology or medicine, and to visionary individuals who produced and incorporated new elements into transsphenoidal surgery. And so while the new endoscopic technique brings forth new challenges, its development reaffirms the principles laid down by the pioneers of transsphenoidal surgery.