The discovery of the phenomenon of anesthesia over 150 years ago was a watershed event that revolutionized the practice of medicine. Despite their annual use in millions of patients, the mechanism by which volatile anesthetics produce reversible loss of consciousness remains a mystery. The inherent problems in studying loss of consciousness in humans are legion. However, multiple model organisms are currently being exploited to apply the powerful tools of modern molecular genetics to this question. Mutants in yeast, nematodes, fruit flies and mice have been produced that display abnormalities in their response to volatile anesthetics. Each organism possesses unique advantages and difficulties as a model system, and each reveals different molecules that control its response to anesthetics. Nonetheless, the accumulating body of genetic evidence points to multiple targets for volatile anesthetics. Not only will understanding how volatile anesthetics work yield better and safer anesthetics, but, in addition, these remarkable compounds may ultimately serve as probes to understand the nature of consciousness itself.