Dysregulation of sodium (Na⁺) balance is a major cause of hypertensive cardiovascular disease. The current dogma is that interstitial Na⁺ readily equilibrates with plasma and that renal excretion and reabsorption is sufficient to regulate extracellular fluid volume and control blood pressure. These ideas have been recently challenged by the discovery that Na⁺ accumulates in tissues without commensurate volume retention and activates immune cells, leading to hypertension and autoimmune disease. However, objections have been raised to this new paradigm, with some investigators concerned about where and how salt is stored in tissues. Further concerns also include how Na⁺ is mobilized from tissue stores, and how it interacts with various organ systems to cause hypertension and end-organ damage. This review assesses these two paradigms of Na⁺ regulation in the context of inflammation-mediated hypertension and cardiovascular disease pathogenesis. I also highlight future perspectives and important gaps in our understanding of how Na⁺ is linked to inflammation and hypertension. Understanding mechanisms of salt and body fluid regulation is the sine qua non of research efforts to identify therapeutic targets for hypertension and cardiovascular disease.