Lithium exerts an inhibitory effect on glucose and amino acid-induced insulin release. The inhibitory effect of Li+ persists even in subsequent Li+-free conditions, indicating an only slowly reversible effect. Lithium fails to inhibit glucagon-induced insulin release. The exact mechanism of the lithium effect is as yet undetermined, but interference with calcium flux and/or microtubular function is an attractive hypothesis. The inhibitory effect of lithium on insulin release cannot be reversed by alteration in ionic (Ca++, Mg++, K+) concentrations in the incubation media. Studies involving the effect of low sodium on insulin release in which lithium had been used as an osmotic replacement for sodium must be carefully reassessed because of these findings.