Hypothermia is defined as a drop in temperature below the homeostatic range of cells and tissues. This elicits a response in mammalian cells geared towards cellular and metabolic adaptation. Hibernating mammals provide natural models of cold tolerance and adaptation. Mammalian cells across species share signaling mechanisms for adaptation to hypothermic stimuli. Key molecular mediators of hypothermic signaling, including: (i) cold-sensing ion channels such as TRPM8 and TRPA1, which link temperature changes to calcium signaling and thermoregulatory responses; (ii) β-adrenergic signaling and uncoupling protein 1 (UCP1)-mediated non-shivering thermogenesis in brown adipose tissue; (iii) cold-induced epigenetic modifications such as histone acetylation, DNA methylation, and enhancer activation that imprint transcriptional memory of cold exposure; and (iv) RNA-binding proteins CIRBP and RBM3, which are rapidly induced during mild-to-moderate hypothermia and confer neuroprotection, enhance differentiation, and modulate metabolism. Together, these findings outline a molecular framework by which mammalian cells sense, respond, and adapt to cold, with implications for neuroprotection, metabolic health, and therapeutic hypothermia.