Hyperammonemia is the pathological accumulation of ammonia in the blood, which can occur in many different clinical settings. Most commonly in adults, hyperammonemia occurs secondary to hepatic dysfunction; however, it is also known to be associated with other pathologies, surgeries, and medications. Although less common, hyperammonemia has been described as a rare, but consistent complication of solid organ transplantation. Lung transplantation is increasingly recognized as a unique risk factor for the development of this condition, which can pose grave health risks-including long-term neurological sequelae and even death. Recent clinical findings have suggested that patients receiving lung transplantations may experience postoperative hyperammonemia at rates as high as 4.1%. A wide array of etiologies has been attributed to this condition. A growing number of case studies and investigations suggest disseminated opportunistic infection with Ureaplasma or Mycoplasma species may drive this metabolic disturbance in lung transplant recipients. Regardless of the etiology, hyperammonemia presents a severe clinical problem with reported mortality rates as high as 75%. Typical treatment regimens are multimodal and focus on 3 main avenues of management: (1) the reduction of impact on the brain through the use of neuroprotective medications and decreasing cerebral edema, (2) augmentation of mechanisms for the elimination of ammonia from the blood via hemodialysis, and (3) the diminishment of processes producing predominantly using antibiotics. The aim of this review is to detail the pathophysiology of hyperammonemia in the setting of orthotopic lung transplantation and discuss methods of identifying and managing patients with this condition.