Identification of mutations within the phenylalanine hydroxylase gene which cause phenylketonuria has introduced the possibility of diagnosing phenylketonuria by direct analysis of the genome. Genotypic analysis could be used for identifying homozygotes in the newborn period, for prenatal diagnosis, or for heterozygote detection in general populations. Establishing the clinical utility of genotypic diagnosis, however, will require characterization of the cohort of patients identified by genotypic diagnosis, correlation of mutant genotypes with specific biochemical and developmental phenotypes, and consideration of how genotypic diagnosis might contribute to improving the clinical outcome in individuals at risk for mental retardation due to hyperphenylalaninemia.