HIF-1 is commonly activated in human cancers, causing widespread changes in gene expression with enhanced glycolysis and increased angiogenesis. Carbonic anhydrase IX (CAIX), a surface membrane carbonic anhydrase, is a striking HIF target in many tumors, and is presumed to increase the tumor cells ability to adapt to survive. The HIF activation is largely due to local hypoxia, reflecting an inadequate vascular supply and high levels of oxygen consumption by the tumour cells. In addition, many oncogenic events lead to some activation of HIF in the presence of oxygen. The clearest example is loss-of-function of the von Hippel Lindau tumor suppressor protein, which is the ubiquitin E3 ligase recognition component responsible for inactivating HIF in the presence of oxygen. Families with mutations in VHL are affected by the VHL syndrome, with a high risk of clear cell renal cell carcinoma (CCRCC). The clinical manifestations show somatic inactivation of the remaining normal VHL allele, and constitutive HIF activation. Importantly, the great majority of non-familial CCRCC also show biallelic VHL inactivation. We have investigated apparently normal tissue from VHL patients using immunohistochemistry for CAIX and shown that there are numerous pre-malignant foci of cells which show constitutive activation of HIF-1. This provides a way of asking what the consequences of full activation of HIF-1 are in "normal" human cells, and how this leads to tumorigenesis.