This document summarizes the history and treatment of phenylketonuria (PKU). It describes the discovery of PKU in the 1930s and milestones that led to newborn screening starting in the 1960s. Untreated PKU causes intellectual disability, but treatment involving a phenylalanine-restricted diet or medications can prevent disability. Current treatments include dietary therapy, cofactor therapy with sapropterin, and enzyme therapy with phenylalanine ammonia lyase. Gene therapy is also being explored. Newborn screening programs have helped identify thousands of cases annually to facilitate early treatment and prevention of intellectual disability.