The evidence for disturbances of tryptophan and 5-hydroxytryptamine in depression and for various mechanisms by which such disturbances could occur is discussed. Two recent relevant studies in the author's laboratory are described: a) non-esterified fatty acid and total and free tryptophan were determined in plasmas of psychiatric patients unselected with respect to psychiatric diagnosis before and after a stress situation. Retarded patients had significantly low total and free tryptophan values which correlated negatively with agitation. Total tryptophan fell significantly after stress in the non-retarded subjects. The only biochemical abnormality significantly associated with a diagnosis of primary depression was the rise of plasma non-esterified fatty acid after stress. Thus tryptophan abnormalities were associated more with psychiatric rating scores than with diagnoses. b) Determinations on plasma and lumbar and ventricular CSF from psychiatric patients undergoing psychosurgery indicate that low plasma free tryptophan concentrations are associated with decreased 5HT turnover in the central nervous system.