Metabolic rate depression is an important survival strategy for many animal species and a common element of hibernation, torpor, estivation, anoxia and diapause. Studies of the molecular mechanisms that regulate reversible transitions to and from hypometabolic states have identified principles of regulatory control. These control mechanisms are conserved among biologically diverse organisms and include the coordinated reduction of specific groups of key regulatory enzymes or proteins in the cell, a process likely driven by microRNA target repression/degradation. The present review focuses on a growing area of research in hypometabolism and mechanisms involving the rapid and reversible control of translation facilitated by microRNAs. The analysis draws primarily from current research on three animal models: hibernating mammals, anoxic turtles and freeze-tolerant frogs (with selected examples from multiple other sources). Here, we demonstrate a link between metabolic rate depression, a well-documented response to periods of environmental stress, and microRNA expression. Microarray-based expression profiles and PCR-driven studies have revealed that specific microRNAs are induced in response to environmental stress. Selected members of this group decrease pro-apoptotic signaling, reduce muscle wasting and reduce protein translation, whereas other members contribute to cell cycle arrest and mitogen-activated protein kinase signaling. Many of the same microRNAs are frequently deregulated in numerous disease pathologies and, hence, the hypometabolism model could provide a novel approach for the treatment of stroke and heart attack in humans.