The cytotoxicity in the brain of potent selective and non-selective inhibitors of Na+/K+ ATPase has been assessed. Following injection of cardiac glycosides into the dorsal hippocampus of rats, the extent of neuronal loss roughly paralleled their potencies as inhibitors of the enzyme. Dihydroouabain was less potent than ouabain as a cytotoxin by an order of magnitude, similar to their relative affinities for Na+/K+ ATPase. The non-specific inhibitors, melittin, erythrosin B and zinc (chloride) were less neurocytotoxic than the selective inhibitors having equivalent potencies. The toxicity of a low dose of ouabain appeared to be selective for neuronal perikarya as staining for acetylcholinesterase (present on the nerve terminals of the afferent cholinergic innervation) was unaffected. A higher dose of ouabain caused a non-specific necrosis including damage to the neuropil and a loss of cholinesterase staining. Concurrently, there was an invasion of the tissue by cells resembling foaming macrophages. Other inhibitors of the enzyme caused a mixed pathology with both types of responses evident. It is suggested that the pathological response may depend on the relative degrees to which the glial and neuronal activities of the enzyme are affected.