The pharmacological actions of lithium and magnesium have been investigated using isolated smooth muscle preparations from the rat gastrointestinal tract. Tissue contraction was evoked by means of carbachol or electrical field stimulation and the degree of inhibition of contraction caused by lithium was measured. Lithium effects were compared with those of the chemically similar ions, magnesium and calcium, by manipulation of the physiological buffer solutions. Lithium antagonism was enhanced when tissue contractile mechanisms were dependent on extracellular calcium concentration in the bathing fluid. This suggests that lithium is acting at the cell membrane by preventing calcium entry via ion channels. These results are consistent with evidence from clinical studies which indicate low cellular accumulation of lithium at therapeutic concentrations.