Abstract Cancers arising from dysregulation of generally operative signaling pathways are often tissue specific, but the mechanisms underlying this paradox are poorly understood. Based on striking cell-type specificity, we postulated that these mechanisms must operate early in cancer development and set out to study them in a model of von Hippel Lindau (VHL) disease. Biallelic mutation of the VHL ubiquitin ligase leads to constitutive activation of hypoxia inducible factors HIF1A and HIF2A and is generally a truncal event in clear cell renal carcinoma. We used an oncogenic tagging strategy in which VHL-mutant cells are marked by tdTomato, enabling their observation, retrieval, and analysis early after VHL-inactivation. Here, we reveal markedly different consequences of HIF1A and HIF2A activation, but that both contribute to renal cell-type specific consequences of VHL-inactivation in the kidney. Early involvement of HIF2A in promoting proliferation within the proximal tubular epithelium supports therapeutic targeting of HIF2A early in VHL disease.