Abstract: Exposure of fish to hypothermia stress may lead to damage to biological molecules, cells and tissues, and even death. When fish cells sense the cold stress, the cold signals are transduced into the nuclear by a variety of routes to trigger the cold stress responses. A new homeostasis will be established and the resistance of the cells to cold stress will be enhanced through these finely regulated stress responses. The endocrinology system of fish can be activated by cold stress to release hormones such as cortisol and thyroid. These hormones regulate metabolism, osmolarity and immune responses of the body and ultimately lead to alterations in physiology and behavior. Cold stress responses of fish are complexly regulated at multiple levels, including epigenetics, transcription, translation, alternative splicing of pre-mRNAs and post-translational modification of proteins. Recent omics studies have identified many cold responsive genes and metabolism pathways. Energy generation and anti-oxidation responses are critical for the establishment of fish cold resistance. Environmental factors including hypoxia and salinity, and the physiology of the fish such as fasting and nutritious status also can affect the responses and resistance of fish to cold stress. The identification of cold resistance-associated biomarkers and the discovery of functional mechanisms of the linked genes have paramount significance for the breeding of cold-resistant fish strains.