Estivation is a state of aerobic hypometabolism used by organisms to endure seasonally arid conditions, often in desert environments. Estivating species are often active for only a few weeks each year to feed and breed and then retreat to estivate in sheltered sites, often underground. In general, estivation includes a strong reduction in metabolic rate, a primary reliance on lipid oxidation to fuel metabolism, and methods of water retention, both physical (e.g. cocoons) and metabolic (e.g. urea accumulation). The present review focuses on several aspects of metabolic adaptation during estivation including changes in the activities of enzymes of intermediary metabolism and antioxidant defenses, the effects of urea on estivator enzymes, enzyme regulation by reversible protein phosphorylation, protein kinases and phosphatases involved in signal transduction mechanisms, and the role of gene expression in estivation. The focus is on two species: the spadefoot toad, Scaphiopus couchii, from the Arizona desert; and the land snail, Otala lactea, a native of the Mediterranean region. The mechanisms of metabolic depression in estivators are similar to those seen in hibernation and anaerobiosis, and contribute to the development of a unified set of biochemical principles for the control of metabolic arrest in nature.