: Most textbooks state that sodium (Na) accumulation goes hand in hand with fluid retention to maintain the environmental isotonicity. In the last century, several studies found, however, that Na is stored in the extravascular space leading to an activation of the monocyte phagocytic system cells that work as a regulator of the interstitial electrolyte homeostasis. Na-MRI was developed to quantify noninvasively, accurately and reliably tissue Na content. In this review, we give an up-to-date overview of clinical studies utilizing this Na-MRI technique to elucidate the importance of tissue Na content in patients with cardiovascular risk factors leading to microvascular and macrovascular complications. Na storage leads ultimately to organ damage such as left ventricular hypertrophy or hypertrophic vascular remodeling of resistance vessels. Elevated Na content in muscle and skin has been detected in patients with treatment resistant hypertension, type 2 diabetes mellitus, acute and chronic heart failure, chronic kidney disease and end-stage renal failure. Pharmacological interventions have shown that a mobilization of extracellular accumulated Na is possible and may emerge as a new therapeutic approach in some diseases.