Aquatic environments exhibit wide temporal and spatial variations in oxygen levels compared to terrestrial environments. Fish are an excellent model for elucidating the underlying mechanisms of hypoxia adaptation. Over the past decade, several hypoxia-related proteins have been reported to act in concert to convey oxygen change information to downstream signaling effectors. Some signaling pathways, such as redox status, AMPK, MAPK and IGF/PI3K/Akt, are known to play a central role in hypoxia adaptation. These networks regulate oxygen-sensitive transcription factors which, in turn, affect the expression of hypoxia adaptation-related genes. This review summarizes current insights into hypoxia adaptation-related proteins and signaling pathways in fish.