Hypoalbuminemia is frequently observed in hospitalized patients and it can be associated with several different diseases, including cirrhosis, malnutrition, nephrotic syndrome and sepsis. Regardless of its cause, hypoalbuminemia has a strong predictive value on mortality and morbidity. Over the years, the rationale for the use of albumin has been extensively debated and the indications for human serum albumin supplementation have changed. As the knowledge of the pathophysiological mechanisms of the pertinent diseases has increased, the indications for intravenous albumin supplementation have progressively decreased. The purpose of this brief article is to review the causes of hypoalbuminemia and the current indications for intravenous administration of albumin. Based on the available data and considering the costs, albumin supplementation should be limited to well-defined clinical scenarios and to include patients with cirrhosis and spontaneous bacterial peritonitis, patients with cirrhosis undergoing large volume paracentesis, the treatment of type 1 hepatorenal syndrome, fluid resuscitation of patients with sepsis, and therapeutic plasmapheresis with exchange of large volumes of plasma. While albumin supplementation is accepted also in other clinical situations such as burns, nephrotic syndrome, hemorrhagic shock and prevention of hepatorenal syndrome, within these contexts it does not represent a first-choice treatment nor is its use supported by widely accepted guidelines.