Rat peritoneal mast cells were used to study the effects of digitalis glycosides on potassium uptake and histamine release induced by compound 48/80, substance P and egg-albumin (immunological release). In the absence of calcium all glycosides inhibited potassium uptake. Ouabain and digoxin enhanced the histamine release while digitoxigenin either had no effect or was slightly inhibitory. In the presence of calcium, the glycosides only affected potassium uptake and histamine release slightly. In the presence of lithium or lanthanum the enhancement of the histamine release was counteracted. Hydrophilic digitalis glycosides seem to enhance histamine release secondary to an increase in intracellular sodium. Lipophilic glycosides have no effect on the release.