Detoxification of sodium benzoate by elimination as a conjugate with glycine, a nonessential amino acid, provides a pathway for the disposal of waste nitrogen. Since 1979, sodium benzoate has been widely used in the therapeutic regimen to combat ammonia toxicity in patients born with genetic defects in the urea cycle. Although the clinical use of benzoate is associated with improved outcome, the search for biochemical evidence in support of the rationale for benzoate therapy has produced conflicting results. This review begins with an historical account leading to elucidation of the biochemistry of benzoate detoxification and early work indicating the potential utility of the pathway for elimination of waste nitrogen. An introduction to contemporary efforts at employing benzoate to treat hyperammonemia is followed by a detailed review of studies on benzoate metabolism and resultant toxic interactions with other major metabolic pathways. With this background, the several metabolic routes by which benzoate is thought to promote the disposal of waste nitrogen are then examined, followed by a consideration of alternative mechanisms by which benzoate might combat ammonia toxicity.