We then discuss the complex phenotype, after genetic deletion of Setdb1, during early brain development, which is followed by a survey of the role of SETDB1 in cognitive and mood behaviors and its implications for multiple neuropsychiatric disorders, including Huntington’s disease, schizophrenia, depression, Prader-Willi syndrome, and autism spectrum disorder (ASD). This evidence concerns the gene SETDB1 and depressive disorder.