Hypoxia is a potent regulator of a multitude of cellular processes, including metabolism and cell survival. The transcriptional response to oxygen deprivation is mainly mediated by hypoxia-inducible factors (HIFs), which are targeted for proteasomal degradation by the von Hippel-Lindau tumor suppressor protein (pVHL) under normoxia. Podocytes, as part of the glomerular filtration barrier, are prone to hypoxic injury during diseases affecting the glomerulus. VHL and HIF1 were functional in mature murine podocytes in vivo and in vitro, with HIF1 protein stabilization and target gene transcription under both hypoxia and VHL deficiency. Podocyte-specific Vhlh gene loss, mimicking podocyte hypoxia, in young mice of mixed background led to glomerulomegaly and occasional glomerulosclerosis, despite preserved glomerular development. In parallel, hypoxia effects on podocytes in cell culture included increased susceptibility to apoptosis, associated with nuclear translocation of apoptosis-inducing factor (AIF). Similarly, Vhlh gene inactivation in podocytes in vitro resulted in a significant survival disadvantage, particularly in conjunction with additional proapoptotic stimuli. Evaluation of the global transcriptional response to hypoxia in podocytes by microarray analysis revealed a typical upregulation of HIF target genes as well as the induction of genes relevant for stress response, cell-cell, and cell-extracellular matrix interaction. While the lack of a prominent phenotype in young mice with VHL-deficient podocytes is consistent with the absence of specific glomerular manifestations in human VHL disease, a low-oxygen environment of podocytes may contribute to the progression of glomerular disease by altering cellular metabolism and survival.