The effects of epinephrine and electrical stimulation on lipolysis in the skeletal muscles of lean, and obese-diabetic (db/db) mice were studied using the perfused mouse hindquarter preparation. The rate of glycerol release from the obese mouse preparation was two times that of their lean littermates. Epinephrine sensitivity in the db/db mice was reduced only with respect to lipolytic activation, but was unaltered with respect to tissue cyclic AMP elevation and glycogen phosphorylase activation. Electrical stimulation caused a prompt increase in lactate production in both lean and obese mice and elevated glycerol release only in the obese mice. Glycerol release was also increased in the lean mice by stimulating at voltages exceeding 10 volts. Cyclic AMP levels were unaffected by electrical stimulation. Omission of calcium from the perfusion medium severely blunted lipolytic activation by electrical stimulation, which could be restored by calcium readdition. These results suggest that an impairment in lipolytic activation by epinephrine distal to activation of adenylate cyclase exists in the skeletal muscle of young db/db mice. Despite of this impairment, however, lipolysis in the obese mouse muscle was more sensitive to activation by electrical stimulation through a mechanism unrelated to changes in cyclic AMP, but is dependent on extracellular calcium.