A number of carboxylic ionophores stimulate the secretion of norepinephrine from cell suspensions prepared from a transplantable rat pheochromocytoma. The divalent-cation ionophore ionomycin stimulates catecholamine secretion by a mechanism that is dependent upon the presence of extracellular Ca++. It is likely that ionomycin-induced catecholamine secretion results from the ionophore-mediated entry of Ca++ into the cells. The monovalent-cation ionophore monensin stimulates catecholamine secretion by a mechanism that is independent of extracellular Ca++, but is markedly dependent upon extracellular Na+. Monensin probably transports Na+ into the pheochromocytoma cells and increases the intracellular concentration of Na+ in these cells. This rise in intracellular Na+ may cause the release of Ca++ from some intracellular store. Lasalocid stimulates catecholamine secretion by a mechanism that is independent of extracellular Ca++ and is only slightly dependent upon extracellular Na+. The action of lasalocid, in contrast to the actions of ionomycin and monensin, is potentiated by decreased pH. It is likely that lasalocid enters the cells in its uncharged, protonated form. Once inside the cells, lasalocid may promote the release of intracellular Ca++. Alternatively, lasalocid and monensin may stimulate catecholamine secretion by the process which is independent of Ca++. These experiments show that ionophores can stimulate catecholamine secretion by at least three distinct ionic mechanisms.