Acute liver failure(ALF) is characterized by rapid clinical progression with the development of encephalopathy after the onset of jaundice and coagulopathy in a patient without pre-existing chronic liver disease. The acute on chronic liver failure (ACLF) is defined differently in the east than the west. It is a distinct group associated with high 28-day and 90-day mortality. The mortality is governed by the severity of systemic inflammation, sepsis and organ failures in patients with ACLF. The potential for spontaneous recovery is higher for ALF than ACLF. The immune dysfunction in ALF and ACLF patients leads to the development of infections, cerebral edema, and multiorgan dysfunction syndrome, necessitating prompt diagnosis and expedited management in the intensive care unit. A liver support therapy may bridge the liver to spontaneous recovery or liver transplantation. It may be a useful adjunct in the therapeutic armamentarium of management of these patients admitted to the intensive care unit. Recent studies have demonstrated an inhibition of the mitochondrial function in causing organ failures in patients with ACLF. Moreau and colleagues identified a 38-metabolite blood fingerprint specific for patients with ACLF. The fingerprint intensity increased with increase in the ACLF grades. According to the new hypothesis, systemic inflammation in patients with cirrhosis causes multiorgan dysfunction by immunopathology and metabolic dysregulation by reducing the mitochondrial respiration. Therapeutic plasma-exchange (TPE), continuous renal replacement therapy (CRRT) and molecular adsorption and recirculation system (MARS) are the most widely studied modalities of artificial liver support. Randomized controlled trials have demonstrated a survival benefit in ALF patients with TPE. TPE is associated with an improvement in the systemic inflammatory response syndrome, reduced damage-associated molecular patterns (DAMPs), and bacterial endotoxin proinflammatory cytokines, endothelial function, monocyte phagocytic function and oxidative burst capacity in patients with liver failure. The data supporting the benefits of plasma-exchange in patients with ACLF is mainly from China in patients with hepatitis B-related ACLF. In a large multicentric study by the ACLF- Asia Pacific Research consortium the benefits of TPE in patients with ACLF in improving liver-failure related deaths was demonstrated. Even though there are emerging plasma-exchange data in ALF and ACLF, there are many unanswered questions. The exact timing, intensity, strategy (centrifugation versus filtration), and exchange volume (high versus standard) remains an enigma. Combining TPE with CRRT may be a better strategy that needs to be explored in patients with ALF and ACLF.