Family studies indicate that major depressive disorder runs in families, although family members’ risk for other psychiatric disorders may also be increased. Twin and adoption studies suggest that about one-third of the liability for MDD is inherited. Studies investigating individual candidate genes have failed to implicate any single gene in MDD risk. Emerging evidence from genome-wide association studies may identify novel risk genes, although any individual genetic variation appears likely to have only modest effect. Whether focusing on clinical subtypes of MDD, or relying on imaging or other biomarkers rather than clinical features, will expedite the process of gene discovery remains to be determined.