DNA microarray studies done on different fish species exposed to low-oxygen conditions have shown that at the genetic level fish respond to hypoxia by changing the expression of genes involved in oxygen transport, ATP production, and protein synthesis. In the liver of mudsuckers exposed to hypoxia there were changes in the expression of genes involved in heme metabolism such as hemopexin, heme oxygenase 1, and ferritin. Changes in the sequestration and metabolism of iron may suggest hypoxia induced erythropoiesis and increased demand for hemoglobin synthesis, leading to increased oxygen uptake and transport. Increased expression of myoglobin, which is normally only found in muscle tissue, has also been observed after hypoxia exposure in the gills of zebrafish and in non-muscle tissue of the common carp suggesting increased oxygen transport throughout fish tissues.
Microarray studies done on fish species exposed to hypoxia typically show a metabolic switch, that is, a decrease in the expression of genes involved in aerobic metabolism and an increase in expression of genes involved in anaerobic metabolism. Zebrafish embryos exposed to hypoxia decreased expression of genes involved in the citric acid cycle including, succinate dehydrogenase, malate dehydrogenase, and citrate synthase, and increased expression of genes involved in glycolysis such as phosphoglycerate mutase, enolase, aldolase, and lactate dehydrogenase. A decrease in protein synthesis is an important response to hypoxia to decrease ATP demand for whole organism metabolic suppression. Decreases in the expression of genes involved in protein synthesis, such as elongation factor-2 and several ribosomal proteins, have been shown in the muscle of the mudsucker and gills of adult zebrafish after hypoxia exposure .
Research in mammals has implicated hypoxia inducible factor (HIF) as a key regulator of gene expression changes in response to hypoxia  However, a direct link between fish HIFs and gene expression changes in response to hypoxia has yet to be found. Phylogenetic analysis of available fish, tetrapod, and bird HIF-α and -β sequences shows that the isoforms of both subunits present in mammals are also represented in fish Within fish, HIF sequences group close together and are distinct from tetrapod and bird sequences. As well, amino acid analysis of available fish HIF-α and -β sequences reveals that they contain all functional domains shown to be important for mammalian HIF function, including the basic helix-loop-helix (bHLH) domain, Per-ARNT-Sim (PAS) domain, and the oxygen-dependent degradation domain (ODD), which render the HIF-α subunit sensitive to oxygen levels. The evolutionary similarity between HIF sequences in fish, tetrapods and birds, as well as the conservation of important functional domains suggests that HIF function and regulation is similar between fish and mammalian species. There is also evidence of novel HIF mechanisms present in fish not found in mammals. In mammals, HIF-α protein is continuously synthesized and regulated post-translationally by changing oxygen conditions, but it has been shown in different fish species that HIF-α mRNA levels are also responsive to hypoxia. In the hypoxia tolerant grass carp, substantial increases in HIF-1α and HIF-3α mRNA were observed in all tissues after hypoxia exposure. Likewise, mRNA levels of HIF-1α and HIF-2α were hypoxia-responsive in the ovaries of the Atlantic croaker during both short and long term hypoxia.