Marine fish are dehydrated in hyperosmotic seawater (SW), but maintain water balance by drinking surrounding SW if they are capable of excreting the excess ions, particularly Na(+) and Cl(-), absorbed with water by the intestine. An integrative approach is essential for understanding the mechanisms for SW adaptation, in which hormones play pivotal roles. Comparative genomic analyses have shown that hormones that have Na(+)-extruding and vasodepressor properties are greatly diversified in teleost fish. Physiological studies at molecular to organismal levels have revealed that these diversified hormones are much more potent and efficacious in teleost fish than in mammals and are important for survival in SW and for maintenance of low arterial pressure in a gravity-free aquatic environment. This is typified by the natriuretic peptide (NP) family, which is diversified into seven members (ANP, BNP, VNP and CNP1, 2, 3 and 4) and exerts potent hyponatremic and vasodepressor actions in marine fish. Another example is the guanylin family, which consists of three paralogs (guanylin, uroguanylin and renoguanylin), and stimulates Cl(-) secretion into the intestinal lumen and activates the absorptive-type Na-K-2Cl cotransporter by local luminocrine actions. The most recent addition is the adrenomedullin (AM) family, which has five members (AM1, 2, 3, 4 and 5), with AM2 and AM5 showing the most potent or efficacious vasodepressor and osmoregulatory effects among known hormones in teleost fish. Accumulating evidence strongly indicates that members of these diversified hormone families play essential roles in SW adaptation in teleost fish. In this short review, the author has attempted to propose a novel approach for identification of new hormones that are important for SW adaptation using comparative genomic and functional studies. The author has also suggested potential hormone families that are diversified in teleost fish and appear to be involved in SW adaptation through their ion-extruding actions.