In the kidney, cyclooxygenase‐2 (COX‐2) is expressed in the macula densa/cTALH and medullary interstitial cells. The macula densa is involved in regulating afferent arteriolar tone and renin release by sensing alterations in luminal chloride via changes in the rate of Na⁺/K⁺/2Cl⁻ cotransport, and administration of non‐specific cyclooxygenase inhibitors will blunt increases in renin release mediated by macula densa sensing of decreases in luminal NaCl. High renin states [salt deficiency, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers, diuretic administration or experimental renovascular hypertension] are associated with increased macula densa/cTALH COX‐2 expression. Furthermore, there is evidence that angiotensin II and/or aldosterone may inhibit COX‐2 expression. In AT1 receptor knockout mice, COX‐2 expression is increased similar to increases with ACE inhibitors or AT1 receptor blockers. Direct administration of angiotensin II inhibits macula densa COX‐2 expression. Previous studies demonstrated that alterations in intraluminal chloride concentration are the signal for macula densa regulation of tubuloglomerular feedback and renin secretion, with high chloride stimulating tubuloglomerular feedback and low chloride stimulating renin release. When cultured cTALH or macula densa cells were incubated in media with selective substitution of chloride ions, COX‐2 expression and prostaglandin production were significantly increased. A variety of studies have indicated a role for COX‐2 in the macula densa mediation of renin release. In isolated perfused glomerular preparations, renin release induced by macula densa perfusion with a low chloride solution was inhibited by a COX‐2 inhibitor but not a COX‐1 inhibitor. In vivo studies in rats indicated that increased renin release in response to low‐salt diet, ACE inhibitor, loop diuretics or aortic coarctation could be inhibited by administration of COX‐2‐selective inhibitors. In mice with genetic deletion of COX‐2, ACE inhibitors or low‐salt diet failed to increase renal renin expression, although renin significantly increased in wild type mice. In contrast, in COX‐1 null mice there were no significant differences in either the basal or ACE inhibitor‐stimulated level of renal renin activity from plasma or renal tissue compared with wild type mice. In summary, there is increasing evidence that COX‐2 expression in the macula densa and surrounding cortical thick ascending limb cells is regulated by angiotensin II and is a modulator of renal renin production. These interactions of COX‐2 derived prostaglandins and the renin–angiotensin system may underlie physiological and pathophysiological regulation of renal function.