The small molecule diseases include inborn errors of carbohydrate, ammonia, amino acid, organic acid, and fatty acid metabolism. They are central among the biochemical genetic disorders that may present with life-threatening illnesses during infancy and childhood. Many of these disorders are now detected through routine newborn screening. Internists should be familiar with small molecule metabolic disorders as early diagnosis and therapy may enable many patients to survive into adulthood. Additionally, because some patients may not manifest symptoms until late adolescence or adulthood, recognition of the possibility of an inborn error of metabolism in a patient with unusual signs or symptoms may lead to referral to a metabolic specialist and timely diagnosis and treatment. This module reviews the diagnosis, treatment, and natural history of disorders of amino acid, ammonia, organic acid, and fatty acid metabolism. Figures show the methionine-homocysteine-cysteine pathway and branched-chain amino acid metabolism. This module contains 2 highly rendered figures, 18 references, 53 recommended readings, and 5 MCQs.