Thirty years ago it was observed that the synthesis of serotonin, dopamine and norepinephrine was impaired in untreated phenylketonuria (PKU) as judged either by a decreased concentration in the blood or decreased excretion in the urine of these neurotransmitters, or of their meta10545tes, 5‐hydroxyindoleacetic acid (5‐HIAA) and homovanillic acid (HVA). Fifteen years later, when early treatment of PKU with a phenylalanine restricted diet was routinely introduced, an inverse relationship was found between phenylalanine levels and the urinary excretion of dopamine and serotonin. An inverse relationship between blood phenylalanine levels and cerebrospinal fluid (CSF) concentrations of HVA and 5‐HIAA has repeatedly been reported during the past 10 years. Recently, the effect of the discontinuation of diet in PKU on the synthesis of dopamine, norepinephrine and serotonin has been examined, and the possible relationship between low levels of these neurotransmitters and impaired performance on neuropsychological tests has been evaluated. In some PKU patients the performance on neuropsychological tests of higher integrative function is impaired after discontinuation of diet, especially when blood phenylalanine values exceed 1200 µmol/L, and the patients often complain of lack of concentration and emotional instability. When these patients return to a ‘relaxed’ phenyalanine restricted, tyrosine enriched diet, the impaired neuropsychological and behavioural functions appear to be reversible. One mechanism may involve an impaired synthesis of dopamine and serotonin, as the improvement is accompanied by an increase in dopamine and serotonin excretion and a significant increase in CSF concentrations of HVA and 5‐HIAA. Quite recently it has been observed that supplementation of a free diet with tyrosine (approximately 150 mg/kg) seemed to improve personality, behaviour, reaction time or reaction time variability in patients off diet. Plasma tyrosine and CSF HVA concentrations increased significantly. Plasma phenylalanine levels remained high (>1200 µmol/L). Supplementation of a normal diet with tyrosine and tryptophan may prevent mental and neuropsychological dysfunction following diet discontinuation in PKU.