He shared the 2019 Nobel Prize in Physiology or Medicine for "discoveries of how cells sense and adapt to oxygen availability" with William Kaelin Jr. and Peter J.

[7] Semenza became the founding director of the Vascular Program at the Johns Hopkins Institute for Cell Engineering following his post-doctorate.

[7] While a post-doctorate researcher at Johns Hopkins, Semenza evaluated gene expression in transgenic animals to determine how this affected the production of erythropoietin (EPO), known to be part of the means for the body to react to hypoxia, or low oxygen levels in the blood.

Semenza's work showed that the HIF proteins consisted of two parts; HIF-1β, a stable base to most conditions, and HIF-1α that deteriorated when nominal oxygen levels were present.

[12] Semenza's research overlapped with that of William Kaelin and Peter J. Ratcliffe on determining the mechanism of oxygen detection in cells, and how EPO production is regulated by HIF and other factors.

[18][19][20][21] Semenza is married to Laura Kasch-Semenza, whom he had met while at Johns Hopkins, and who currently operates one of the university's genotyping facilities.