Hibernating ground squirrels survive physiological deviations so removed from the mammalian norm that they inevitably lead to death in non-hibernators. In 13-lined ground squirrels and other circannual, or obligate, hibernators, a season of homeothermy that begins with reproduction and ends with obesity is segregated from a season of hibernation. Hibernation is characterized by cycles between extended (~2 weeks) bouts of torpor, punctuated by short (12 hr) arousals to typical euthermic conditions that are superimposed upon months of continuous fasting and inactivity. In torpor, the hibernating mammal exhibits profound drops in heart rate from a few hundred to a few beats/min, metabolic rate to a few percent of active, and core body temperature from 37°C to near zero. Remarkably, the physiological depressions are spontaneously reversed without harm during each arousal. Moreover, at the end of hibernation, the animal returns to homeothermy with surprisingly little muscle, gut or bone disuse atrophy. Clearly, numerous features of the hibernation phenotype would be beneficial if they could be harnessed and applied to humans. Because superimposition of hibernating species on the mammalian phylogeny implies that the common ancestor of all mammals was a hibernator (6), the possibility of deriving useful therapies that mimic various aspects of the hibernation phenotype is within the realm of science, and not merely science fiction. The first step towards achieving this goal is to define the molecular pathways and mechanisms used during natural hibernation to orchestrate and manage their remarkable phenotypic plasticity. Because hibernation’s varied phenotypes are so distinctive, it is unlikely that hypothesis-driven work based on understanding of non-hibernators will provide the transformative data needed to understand hibernation at a molecular level. Our approach to this problem is to interrogate a precisely timed set of samples from 13-lined ground squirrels representing hibernation’s major physiological phenotypes for biochemical differences. Our working hypothesis is that hibernation is a cycle-within-a-cycle, with the torpor-arousal cycles being embedded within a summer-winter seasonal cycle. This model predicts a resetting of baseline physiology between the summer and winter modes that leads to tissue protection and that it is only in the protected winter state that torpor can be elicited. To test the predictions of this hypothesis and identify the underlying molecular mechanisms, we have collected an extensive tissue bank representing multiple timepoints throughout the year that represent key transitions in both cycles together. These samples are being examined with high-throughput ‘omics’ methodologies to identify the metabolites, proteins and transcripts in multiple organs that are candidates to support and drive the remarkable physiological transitions of hibernation. Early data support our model of an altered baseline physiology that separates winter from summer animals and reveal a surprising degree of tissue-specific variation that reflects unique aspects of organ function in the changes observed (1-5).