Because of the torturous vasculature of solid tumors and the diffusion limitations of oxygen, cancer cells routinely encounter hypoxic conditions. Immunohistochemistry of pimonidazole hydrochloride, a nitroimidazole with hypoxic selectivity, identifies a ring of cells (brown) that define the hypoxic border between well-oxygenated and necrotic tissue. Cancer cells depend on glycolysis to meet energetic demands when deprived of oxygen; as a result, these hypoxic regions are expected to be acidic. In response to acidic environments, cells exhibit chronic elevated autophagic activity, a phenotype that is partially reversible in vivo following buffer therapy with sodium bicarbonate. For details, see article by Wojtkowiak and colleagues on page 3938.