Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. The oxygen-sensitive hypoxia inducible factor (HIF) transcriptional regulators HIF-1alpha and HIF-2alpha are overexpressed in many human NSCLCs, and constitutive HIF-2alpha activity can promote murine lung tumor progression, suggesting that HIF proteins may be effective NSCLC therapeutic targets. To investigate the consequences of inhibiting HIF activity in lung cancers, we deleted Hif-1alpha or Hif-2alpha in an established Kras(G12D)-driven murine NSCLC model. Deletion of Hif-1alpha had no obvious effect on tumor growth, whereas Hif-2alpha deletion resulted in an unexpected increase in tumor burden that correlated with reduced expression of the candidate tumor suppressor gene Scgb3a1 (HIN-1). Here, we identify Scgb3a1 as a direct HIF-2alpha target gene and demonstrate that HIF-2alpha regulates Scgb3a1 expression and tumor formation in human Kras(G12D)-driven NSCLC cells. AKT pathway activity, reported to be repressed by Scgb3a1, was enhanced in HIF-2alpha-deficient human NSCLC cells and xenografts. Finally, a direct correlation between HIF-2alpha and SCGB3a1 expression was observed in approximately 70% of human NSCLC samples analyzed. These data suggest that, whereas HIF-2alpha overexpression can contribute to NSCLC progression, therapeutic inhibition of HIF-2alpha below a critical threshold may paradoxically promote tumor growth by reducing expression of tumor suppressor genes, including Scgb3a1.