Evidence is presented to support the hypothesis that submillimolar concentrations of methylxanthines stimulate Na+, K(+)-ATPase activity in skeletal muscle. Administration of methylxanthines to skeletal muscle results in plasma membrane hyperpolarization and increased rates of K+ uptake and Na+ efflux. These effects are both dose- and time-dependent and inhibited by blockers of the Na+, K+ ATPase. The mechanisms for stimulation of Na+, K(+)-ATPase activity and the signal transduction pathways are not known. The methylxanthine concentrations required for stimulation of Na+, K(+)-ATPase activity are less than those required to cause a 50% inhibition of phosphodiesterase activity, and therefore increases in cyclic AMP due to inhibition of the enzyme are not involved. Possible mechanisms by which methylxanthines may increase Na+, K(+)-ATPase activity include; (1) a role for increased intracellular [Ca2+]; (2) Ca2+ or adenosine-receptor-mediated increases in intracellular cyclic AMP; and (3) a direct action of methylxanthines on the Na+, K+ ATPase.