Major depressive disorder (MDD) has been associated with abnormally reduced function of central serotonergic systems by various types of evidence. One instructive paradigm for investigating the relationship between serotonergic function and depression has involved the mood response to tryptophan depletion (TD), achieved by oral loading with all essential amino acids excepting the 5-HT precursor, tryptophan. We obtained preliminary evidence that the mood lowering effect of TD depends upon the genotype for a functional polymorphism in the promoter region of the 5-HT transporter (5-HTT), designated 5-HTTLPR, as well as upon family history. In healthy females the s-allele and a positive family history for mood disorders appeared to be additive risk factors for the development of depressive symptoms during TD.