Phenylketonuria (PKU) is a rare, but serious, metabolic disease that can cause a variety of neurological, psychological, and academic complications. Fortunately, many individuals with PKU who are identified and treated early can go on to live a relatively normal life. However, PKU does continue to present with a variety of complex underlying factors that school psychologists must consider. Diet and the corresponding psychosocial complexities cause difficulties for students within the schools. Neuropsychological and academic impairments, such as math and reading comprehension, also tend to pose challenges that may require intervention. Moreover, emotional, and comorbid behavioral conditions must be accurately identified and treated within the schools to prevent more severe consequences for these children. Appropriate assessments and ongoing monitoring of individuals with PKU must also be taken into consideration when working in the schools. Finally, individuals such as refugee or immigrant children who come from economically disadvantaged or non-Western societies and may have had less access to thorough medical care should not be overlooked when considering PKU in the schools.