The aim of this work was to study in mammals the ability of high pressures to reverse the anesthesia produced by a wide range of general anesthetics. Dose–response curves were obtained using mice at pressures ranging from 1 to 125 atm for five agents, namely α-chloralose, ethylcarbamate, phenobarbital and, for comparison, nitrogen and argon. The increase of ED50 was found to be a linear function of pressure in each case, but the proportionate increases in ED50 with pressure were greater for the three non-inhalation agents than for the two gases. Thus, the ratio of ED50 at 100 atm to that at 1 atm was 1.74 for α-chloralose, 1.68 for ethylcarbamate, and 1.54 for phenobarbital. On the other hand, the corresponding ratios for argon and nitrogen were only 1.36 and 1.34. The potencies of three short-acting agents (trichloroethanol, ketamine, and alphadione) were shown to increase with decreasing pressure, although ED50 values could not be obtained. It is concluded that pressure reverses the actions of a wide variety of anesthetics in mice. The results of this study are not inconsistent with either the fluidized lipid membrane or the critical volume hypotheses of anesthetic action.