This study describes the tolerance characteristics of barbital compared to pentobarbital, the standard drug, during "chronically equivalent" treatment. Barbiturate tolerance was assessed as the increase in dose from the beginning to the end of treatment required to achieve equieffective peak effect. Dispositional tolerance was assessed as a reduction in the elimination half-life of barbiturate from blood. Functional tolerance was assessed as the increase in blood concentration of barbiturate at the time of peak effect. Overall, greater tolerance was developed to pentobarbital than to barbital. For pentobarbital, tolerance was both dispositional and functional; the dispositional tolerance developed rapidly and was almost complete at 1 week. For barbital, tolerance was exclusively functional. A most interesting finding was that functional tolerance to barbital and pentobarbital developed at the same slow rate for chronically equivalent treatment. This finding suggests that functional tolerance development is independent of the particular barbiturate reflecting the adaptability of the central nervous system to chronic depression.