In order to evaluate the possible role of sodium- and potassium-activated adenosine triphosphatase in the active transport of sodium by the renal tubules, we examined the effect of large changes in the tubular reabsorptive load of sodium on the Na-K-ATPase activity of rat kidney homogenates. Glomerular filtration and tubular reabsorption of sodium per gram of kidney tissue increased progressively after contralateral uninephrectomy. This was paralleled by an increase in Na-K-ATPase per milligram of protein in a microsomal fraction of kidney cortex. The importance of this change is underlined by the absence of simultaneous increases in other microsomal enzymes such as glucose-6-phosphatase and Mg(++)-dependent ATPase, or in succinic dehydrogenase or glutaminase. Similar increases in Na-K-ATPase were observed when the net tubular reabsorption of sodium was increased by feeding the animals a high-protein diet or after injection of methylprednisolone. On the other hand, Na-K-ATPase was lowered when tubular transport of sodium was reduced by bilateral adrenalectomy. The results of these experiments show that renal Na-K-ATPase changes in an adaptive way when renal reabsorption of sodium is chronically increased or diminished and support the hypothesis that this enzyme system is involved in the process by which sodium is actively transported across the renal tubule.