Major depressive disorder (MDD) is common and moderately heritable. Recurrence and early age at onset characterize cases with the greatest familial risk. Major depressive disorder and the neuroticism personality trait have overlapping genetic susceptibilities. Most genetic studies of MDD have considered a small set of functional polymorphisms relevant to monoaminergic neurotransmission. Meta-analyses suggest small positive associations between the polymorphism in the serotonin transporter promoter region (5-HTTLPR) and bipolar disorder, suicidal behavior, and depression-related personality traits but not yet to MDD itself. This polymorphism might also influence traits related to stress vulnerability. Newer hypotheses of depression neurobiology suggest closer study of genes related to neurotoxic and neuroprotective (neurotrophic) processes and to overactivation of the hypothalamic-pituitary axis, with mixed evidence regarding association of MDD with polymorphisms in one such gene (brain-derived neurotrophic factor [BDNF]). Several genome-wide linkage studies of MDD and related traits have been reported or are near completion. There is some evidence for convergence of linkage findings across studies, but more data are needed to permit meta-analysis. Future directions will include more intensive, systematic study of linkage candidate regions and of the whole genome for genetic association; gene expression array studies; and larger-scale studies of gene-environment interactions and of depression-related endophenotypes.