 These guidelines aim to optimize and standardize PKU care by providing professionals with evidence-based recommendations on managing this autosomal recessive-inborn error of phenylalanine metabolism, which can cause severe intellectual disability, epilepsy, and behavioral problems if left untreated. The guidelines were developed using the Agree method and Assign method for literature search, critical appraisal, and evidence grading. The Delphi method was used when there was little evidence available. The level of evidence for most recommendations is C or D, although study designs and patient numbers are suboptimal, many statements are convincing, important, and relevant. Knowledge gaps have been identified that require further research to improve care for PKU patients in the future. This article was authored by A.M. J. van Wegberg, MacDonald, K. R. Ring, and others.