Extended treatment of rats with lithium inhibits the increase in the number of extrajunctional acetylcholine receptors that occurs in their denervated skeletal muscle. In normal muscle, lithium reduces the number of acetylcholine receptors at neuromuscular junctions. These changes appear to be a relatively specific effect of lithium on the turnover of receptors. Skeletal muscle provides an accessible system for analyzing the role of lithium (and other cations) in the regulation of cell surface receptors. This regulation may play a role in the mechanism by which lithium prevents recurrent manic-depressive episodes.