1. Cortex-free adrenal glands previously labelled with the isotope (45)Ca have been perfused with Locke or modified Locke solution to assess Ca(2+) movements under different conditions.2. Substitution of Na(+) by either sucrose or choline during perfusion with Ca(2+)-free Locke solution induced a significant and sustained decrease in the (45)Ca efflux. Concomitant with this effect there was an increase in the output of catecholamines from the perfused gland.3. In the presence of Ca(2+) (2.2 mM) in the perfusion fluid, Na(+) omission induced an increase in the (45)Ca efflux. This increase was significantly reduced if 3 x 10(-4)M methoxyverapamil (D-600) was present in the perfusion fluid. However, the increased catecholamine output in response to Na(+) deprivation remained unchanged.4. Excess of Mg(2+) (20 mM) in the extracellular medium blocked the increase in catecholamine output in response to Na(+) omission. However, the decrease in the (45)Ca efflux produced by Na(+) deprivation in the presence of this high concentration of Mg(2+) was similar to that observed in the presence of 1.2 mM-Mg(2+).5. In the absence of Mg(2+) in the extracellular medium, substitution of Na(+) by either sucrose or choline induced a sharp and transient increase in the (45)Ca efflux rate coefficient. This increased (45)Ca efflux, which has similar time course as the enhanced catecholamine output, was not affected by the presence of 3 x 10(-4)M methoxyverapamil.6. In the absence of Mg(2+), the graded substitution of Na(+) in the perfusion medium by sucrose enhanced the efflux of (45)Ca. This increase in the (45)Ca outward movement was linearly related to the logarithm of the extracellular Na(+) concentration.7. After perfusion of glands with Ca(2+)-free Locke solution, the reintroduction of Ca(2+) (2.2 mM) into the perfusion fluid produced an increase in the (45)Ca efflux. This was accompanied by a discharge of catecholamines.8. Although Mg(2+) (20 mM) was effective in blocking catecholamine release, this divalent cation did not modify the increase in the (45)Ca efflux produced by Ca(2+) reintroduction.9. In contrast to these later observations, methoxyverapamil (3 x 10(-4)M) was effective in inhibiting both increases in catecholamine output and (45)Ca efflux in response to Ca(2+) reintroduction.10. It is concluded from these experiments that (a) Ca(2+) movements in the adrenal medulla may involve both Na(+)-Ca(2+) and Ca(2+)-Ca(2+) exchange mechanisms; (b) the omission of Na(+) from the extracellular environment produces not only an increase in the output of catecholamines but it may increase the intracellular levels of Ca(2+) and that this may result in an increased Ca(2+) efflux when Mg(2+) is omitted from the perfusion fluids, and that (c) the competition between Ca(2+) and Mg(2+) during the secretory process may involve an intracellular site.