Cancer is a disease of genomic aberration. The hypoxic microenvironment is believed to promote tumor progression via the induction of genetic instability. To understand how hypoxia drives tumor progression, we have shown recently that the hypoxia-inducible transcription factor, HIF-1alpha, is critical for transcriptional repression of DNA repair genes by a noncanonical mode of action referred to as the "HIF-1alpha-c-Myc axis." HIF-1alpha action via the HIF-1alpha-c-Myc axis is independent of its DNA-binding and transactivation domains; instead it requires the PAS-B domain to displace the transcription activator c-Myc from the target gene promoter for gene repression. Owing to the functional compromise on DNA repair, tumor cells with activated HIF-1alpha-c-Myc axis display persistent DNA damage, genetic alterations, and malignant progression. However, apoptosis-proficient cells are resistant to such changes. These findings argue that the hypoxic microenvironment plays a critical role in driving genetic alterations especially in apoptosis-deficient cells for malignant progression.