Hyperammonemia leads to neurotoxic levels of brain ammonia and is a major factor involved in the pathogenesis of hepatic encephalopathy (HE). Ammonia-lowering treatments primarily involve two strategies: inhibiting ammonia production and/or increasing ammonia removal. Targeting the gut has been the primary focus for many years, with the goal of inhibiting the generation of ammonia. However, in the context of liver failure, extrahepatic organs containing ammonia metabolic pathways have become new potential ammonia-lowering targets. Skeletal muscle has the capacity to remove ammonia by producing glutamine through the enzyme glutamine synthetase (amidation of glutamate) and, given its large mass, has the potential to be an important ammonia-removing organ. On the other hand, glutamine can be deaminated to glutamate by phosphate-activated glutaminase, thus releasing ammonia (ammonia rebound). Therefore, new treatment strategies are being focused on stimulating the removal of both ammonia and glutamine.