Human serum albumin (HSA) is a multifunctional, non-glycosylated, negatively charged plasma protein with ligand-binding, transport, antioxidant, and enzymatic activities. It is primarily synthesized in the liver and plays a crucial role in maintaining colloid osmotic pressure and microvascular integrity. Clinically, HSA has been used as a plasma expander, but recent meta-analyses and the SAFE study suggest it does not provide a survival benefit over crystalloid solutions in critically ill patients. However, HSA has shown encouraging results in volume expansion and dialysis therapy for patients with liver disease. This review discusses the current understanding of HSA therapy in critical care and hepatology, its potential applications, and potential contraindications. HSA's tertiary structure, ligand-binding properties, antioxidant functions, anti-inflammatory effects, and metal-binding capabilities are detailed, highlighting its complex biochemical properties. The review also explores the use of HSA in critical illness, liver disease, and its potential benefits and risks in specific patient populations.Human serum albumin (HSA) is a multifunctional, non-glycosylated, negatively charged plasma protein with ligand-binding, transport, antioxidant, and enzymatic activities. It is primarily synthesized in the liver and plays a crucial role in maintaining colloid osmotic pressure and microvascular integrity. Clinically, HSA has been used as a plasma expander, but recent meta-analyses and the SAFE study suggest it does not provide a survival benefit over crystalloid solutions in critically ill patients. However, HSA has shown encouraging results in volume expansion and dialysis therapy for patients with liver disease. This review discusses the current understanding of HSA therapy in critical care and hepatology, its potential applications, and potential contraindications. HSA's tertiary structure, ligand-binding properties, antioxidant functions, anti-inflammatory effects, and metal-binding capabilities are detailed, highlighting its complex biochemical properties. The review also explores the use of HSA in critical illness, liver disease, and its potential benefits and risks in specific patient populations.