A method is described for differentiating the phenylalaninaemias based upon blood phenylalanine (phe) responses to ingestion of natural protein diets with standard phe content. A classification scheme derived primarily from these studies is suggested which includes two forms of phenylketonuria (PKU) and four forms of phenylalaninaemia (variants) unrelated to abnormalities in tyrosine metabolism. Dietary therapy is mandatory for types I and II and possibly for type III, but does not appear to be necessary for types IV or V. Evidence provided by family studies supports the concept that the phenylalaninaemias are genetically distinct. The increased incidence of PKU consequent to newborn blood screening programmes may well be related to misdiagnosis as well as to increased recognition of PKU.