The use of antidepressants has been subject to considerable controversy and debate both inside and outside the psychiatric profession. This has led to a situation where not only a substantial portion of lay people and patients but also many psychiatric clinicians are skeptical about their efficacy and safety. The publication of the “serotonin hypothesis” umbrella review in Molecular Psychiatry in 2022 and its coverage in international media has accelerated these debates, and has raised questions about the relationship between the so-called “chemical imbalance” hypothesis and the mechanisms of therapeutic benefit. Critics have argued that the perceived benefit is only because of the placebo effect and “emotional blunting” produced by the medications. On the safety side, there is greater awareness now regarding the risk of complicated and protracted withdrawal and serious adverse effects such as permanent sexual dysfunction. This webinar aims to explore the controversies surrounding the efficacy, safety, and mechanisms of antidepressant medications, with the goal of dispelling misconceptions about antidepressants while acknowledging the ways in which traditional understanding of their use has fallen short. The implications for the use of antidepressants in clinical practice will also be discussed.