Low O2 tension, or hypoxia,activates a complex transcriptional program via hypoxia-inducible factors (HIFs) to facilitate adaptation to low-O2 conditions. This work describes two instances of HIF activity in normal tissue development and disease progression. First, HIF is partly responsible for MYC inhibition in hypoxic human colon carcinoma cells. Hypoxic MYC down-regulation requires the E3 ubiquitin ligases FBXW7 and DDB1, as well as cytosolic cathepsins. Reduced MYC protein correlated with hypoxic inhibition of RNA polymerase III-dependent MYC target genes, suggesting that MYC suppression under hypoxia occurs independently of its binding partner MAX. MYC overexpression in hypoxic cells induced cell death in a NOXA- and PUMA-dependent manner. Therefore, MYC degradation can be an adaptive strategy to promote hypoxic cell survival. Second, murine genetic models revealed an unexpected role for HIFs in the low-O2 environment of the developing epidermis. Mice lacking HIF1α and HIF2α in the epidermis exhibited defective keratinocyte differentiation, impaired epidermal barrier development, and reduced expression of the major cornified envelope gene filaggrin (Flg). Filaggrin expression in hypoxic keratinocytes requires HIF1α and HIF2α, suggesting that one mechanism by which HIF controls epidermal development lies in Flg regulation. Collectively, these data demonstrate that HIF-mediated responses to low O2 tension play important roles in cell survival and differentiation.