Adenosine type 1 receptor (A1‐AR) antagonists induce diuresis and natriuresis in experimental animals and humans. Much of this effect is due to inhibition of A1‐ARs in the proximal tubule, which is responsible for 60–70% of the reabsorption of filtered Na+ and fluid. Intratubular application of receptor antagonists indicates that A1‐AR mediates a portion of Na+ uptake in PT and PT cells, via multiple transport systems, including Na+/H+ exchanger‐3 (NHE3), Na+/PO4− co‐transporter and Na+‐dependent glucose transporter, SGLT. Renal microperfusion and recollection studies have shown that fluid reabsorption is reduced by A1‐AR antagonists and is lower in A1‐AR KO mice, compared to WT mice. Absolute proximal reabsorption (APR) measured by free‐flow micropuncture is equivocal, with studies that show either lower APR or similar APR in A1‐AR KO mice, compared to WT mice. Inhibition of A1‐ARs lowers elevated blood pressure in models of salt‐sensitive hypertension, partially due to their effects in the proximal tubule.