Many tumors are hypoxic, and cells that are experimentally rendered hypoxic display a variety of phenotypes which allow them to adapt to the micro-environment. These phenotypes include a shift from aerobic to anaerobic metabolism, a diminution of reactive oxygen species, an arrest of proliferation, apoptosis, and a secretion of pro-angiogenic growth factors. Some of these hypoxic phenotypes are re-capitulated in normoxic tumor cells (e.g., an increase in anaerobic metabolism), and some tumors have undergone mutations that allow them to bypass the cell cycle arrest and apoptosis typically seen in hypoxic cells. Hypoxic regulation of gene expression is responsible for many hypoxia-induced phenotypes, and here we review a variety of mechanisms by which gene expression is altered in hypoxic cells. These include transcription by HIF-1, the hypoxia inducible transcription factor, and other hypoxia-inducible transcription factors, including ones generated by hypoxic activation of the integrated stress response. Recent data from our laboratory demonstrate that nonsense mediated RNA decay is also regulated in hypoxic cells and thus may play an important role in hypoxic gene regulation and hypoxic phenotypes.