The urea cycle is a vital metabolic process for the safe removal of ammonia, a toxic byproduct of protein metabolism, from the body by converting it into urea for excretion in the urine. Deficient activity of any of the enzymes involved in this process puts the patient at risk of hyperammonemia, a medical emergency that can result in irreversible neurological impairment and death if not properly recognized and treated. Therapeutics, including trigger avoidance, diet modification, and nitrogen scavenger medications, can significantly reduce this risk, but increasingly, more patients are resorting to liver transplantation as a more definitive therapy. In this chapter, we review normal urea cycle metabolism, pathophysiology of the different urea cycle defects, common presentations, differential diagnoses, and treatment options.