Hypoxia is one of the critical abiotic factors in aquatic ecosystems, resulting in significant mortality of invertebrates and fish and billions of dollars in losses to fisheries and aquaculture. Animals possess a limited ability to maintain life functions, including muscular CNS activity, in hypoxia by generating ATP by glycolysis, but this requires constant regeneration of glucose fuel. In the last few years, data started to accumulate showing that gluconeogenesis plays a central role in this process in crustaceans and nematodes, with tissues like the fat body and the hepatopancreas specializing in the regeneration of glucose to feed glycolysis in muscles and the brain, in a process known as the Cori cycle. In the nearly 100 years since the Nobel Prize-winning work of Carl and Gerty Cori, the role of this process has been well characterized in mammals, but we still do not know if it plays a significant role in aquatic invertebrates’ ability to survive hypoxia.