During winter hibernation, small mammals fall into long periods of deep cold torpor where metabolic rate is suppressed by > 90% and core body temperature can fall to near 0 degrees C. Studies with hibernators illustrate the molecular regulatory mechanisms that coordinate the suppression of metabolic functions during torpor, reprioritize energy use, and preserve/stabilize macromolecules to support long-term viability during cold torpor. This review explores mechanisms including posttranslational modification of proteins, differential regulation of enzymes, global suppression of transcription and translation including a role for microRNA, torpor-responsive gene expression, signal transduction, and regulation of transcription factors. The molecular basis of natural torpor in hibernating mammals offers models and applications that are relevant to issues in clinical science including hypothermia and ischemia resistance, inducible torpor, organ preservation, and atrophy resistance.