Hypoxia is a common feature of advanced solid tumors causing cancer progression and resistance to treatment. Hypoxia activates mitophagy as well as macroautophagy that regulates carcinoma cell survival. p62/SQSTM1, a multifunctional protein that targets proteins to degradation by proteasomes and autophagy, is itself downregulated by hypoxia-activated autophagy in carcinoma cells. The hypoxic degradation of p62 is seen across several carcinoma cell lines. In contrast to hypoxic activation of mitochondrial autophagy, the hypoxia-induced degradation of p62 occurs partially independently from the HIF pathway. The finding argues that in addition to transcriptional gene regulation through HIF, autophagy has a central role in the regulation of hypoxic cancer cell survival responses.