Next, we critically assess the recent progress of our understanding of the role of estrogen receptor signaling and its therapeutic effects in psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder (MDD), ASD, ADHD, general anxiety disorder (GAD), post-traumatic stress disorder (PTSD), eating disorders, and substance use disorder, with an aim to provide and highlight the importance of estrogen singling in major psychiatric disorders, thereby possibly providing guidance as to finding new therapeutic targets. The gene discussed is ESR1; the disease is major depressive disorder.