Cells are able to sense the level of oxygen in their environment and can adapt by rapidly altering expression of various genes. This capacity has both positive and negative implications; following ischemic injury, it can help promote blood vessel growth and recovery, but in cancer, new vessel growth helps sustain developing and metastasizing tumors. In the 1990s, William Kaelin Jr. and Gregg Semenza (Figure 1) revolutionized the understanding of cellular oxygen sensing by identifying many of the molecular players involved. Their continuing work in the field has led to the development of successful therapeutic strategies. In April, their contributions will be celebrated as they receive the 2012 ASCI/Stanley J. Korsmeyer Award. The JCI recently spoke to Kaelin and Semenza about their path to this prize. JCI: You’ve both contributed to the understanding of how cells sense and respond to oxygen. What got you into the field? Kaelin: In 1993 I had my eye out for a new line of investigation that would be distinct from the work I did on the retinoblastoma (Rb) tumor suppressor protein as a postdoctoral fellow with David Livingston. A paper describing the isolation of the von Hippel–Lindau (VHL) tumor suppressor gene crossed my desk that summer, and I thought this would be a great gene to work on, in part because some of the approaches I had used to study Rb seemed well suited to study the VHL protein. I was also very familiar with the clinical features of von Hippel–Lindau disease, which include an increased risk of kidney cancer, hemangioblastoma, and pheochromocytoma, from my clinical training. I thought I would like to work on a common cancer and thought that studying the VHL gene would be an inroad into at least one of those (kidney cancer). In addition, I was always struck by the fact that tumors linked to VHL disease are notable for their ability to secrete erythropoietin and to stimulate angiogenesis, both of which are normally induced in tissues that are receiving inadequate oxygen. In the early 1990s, there was considerable excitement about the idea that blocking angiogenesis would have antitumor effects, but our understanding of the molecular control of angiogenesis was fairly rudimentary. The clinical features of VHL disease, it seemed to me, strongly suggested that the VHL gene would be important for the control of angiogenesis and, more broadly, important for cells and tissues to respond appropriately to changes in oxygen (since, in effect, the tumors linked to VHL disease seemed to constantly “think” they were deprived of oxygen). Semenza: When I first came to Johns Hopkins as a postdoctoral fellow, I was interested in studying gene regulation, and decided to study the human erythropoietin (EPO) gene. We engineered a series of transgenic mouse lines that contained the human EPO gene with various amounts of the flanking DNA. We were able to identify sequences that controlled its expression in the liver and kidneys, and sequences that prevented expression in other tissues. From there, we became more interested in studying how transcription of the gene was activated in response to low oxygen conditions. We went into a tissue culture system, and we were able to identify the sequences within the gene that were required for the response to hypoxia. Having found this key DNA sequence, which became known as the hypoxia response element, we thought that it probably contained the binding site for a transcription factor that was required for the activation of a transcription under hypoxic conditions. We used the DNA sequence as a probe to identify a protein that was present only when the cells were exposed to hypoxia and named it …