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Ba ions caused an intense and prolonged discharge of melanocyte-stimulating hormone (MSH) from perifused neurointermediate lobes of mouse pituitaries and dispersed pars intermedia cells. The effect persisted in chronically cultured lobes or cells. It did not require Ca, but, like the Ca-dependent response to excess K, was blocked by cyanide combined with glucose lack. The secretagogue effect of Ba was blocked or prevented by Co or by excess Ca, both of which can reduce inward Ba currents through Ca channels. Prior exposure to excess K partially reduced the secretagogue effect of Ba, suggesting that depolarization caused some inactivation of Ba current. In contrast to Ba, excess K elicited secretion that was transient, and prior exposure of preparations to excess K (in the absence of Ca) profoundly suppressed the secretagogue effect of Ca. The evidence is consistent with the view that inward Ca current rapidly inactivates in these cells. It is concluded that Ba ions have a potent and persistent direct secretagogue effect on the melanotrophs that may reflect, in part, their ability to penetrate Ca channels more easily than Ca ions. The strong secretagogue effects of Ba on melanotrophs may be of considerable utility in studies on MSH secretion since a physiological secretagogue has yet to be discovered. Moreover, since the responses of melanotrophs (and other endocrine cells) to Ba can be distinguished from those of various other secretory cells and neurones, it is suggested that Ba may provide a tool for characterizing the distinctive membrane properties of the Ba-responsive endocrine cells.