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Natural freeze tolerance is an key part of winter cold hardiness for a variety of reptile species that live in seasonally cold climates. However, freezing survival is achieved without the accumulation of high concentrations of colligative cryoprotectants. Instead, reptiles appear to emphasize high anoxia tolerance and well-developed antioxidant defenses to allow endurance of ischemia–reperfusion stress associated with cycles of freeze–thaw. DNA array screening of freeze-responsive gene expression in hatchling painted turtles highlighted the up-regulation of genes/proteins involved in iron sequestering and antioxidant defense, again emphasizing the need to protect cells from oxygen free radical damage during freeze–thaw excursions. Continuing studies of the gene expression responses of turtles to freezing will help to identify the full range of adaptive protein strategies that are key to vertebrate freezing survival and potentially suggest new applied treatments for use in cryomedical applications with transplantable organs.