Albumin is a frequently prescribed drug in hospitalized patients, and its effect on clinical outcomes has been scrutinized in recent years. Data from meta-analyses has suggested harm related to albumin therapy in critically ill patients, and new observational data are consistent with these results. However, appropriately powered randomized, controlled trials have shown albumin to be safe in broad groups of critically ill patients. This article will discuss the reasons for differences between observational and controlled trial data, and the implications for future albumin use and clinical research.