Depression is one of the most thoroughly evaluated diseases in psychiatry with regard to diagnosis as well as treatment variables. Like in other medical conditions, early treatment should be achieved and watchful waiting, which is for instance also not done in the treatment of high blood pressure or diabetes, has not been proven to be a sophisticated approach based on neurobiological considerations. Like in other diseases, it is apparent that days of untreated depression (DUP) may result in brain damage like reduced volume size of the hippocampus. The course of illness of depression shows that life events are less important in later stages of the illness than in earlier. The introduction of the group of selective serotonin reuptake inhibitors (SSRI) marked a revolution in the treatment of depression, since it was possible to treat patient for the first time effectively with a considerably lower side effect profile. Substantially more patients could be reached with this approach and a possible association between usage of SSRIs and the reduction of the suicide rates in different countries like Sweden, Austria and Hungary has been discussed. Dual reuptake inhibitors effecting both the serotonergic as well as the noradrenergic pathways and the dopaminergic noradrenergic medication bupropion have been introduced in the field with specific angles of treatment goals like pain, somatic symptoms or drive. The recently introduced antidepressant agomelatine demonstrates a novel and unique mechanism of action with the combination of melatonergic agonistic as well as serotonergic antagonistic activity exhibiting a more distinct influence on the circadian rhythm compared to other, currently available antidepressants. Deep brain stimulation and vagus nerve stimulation for treatment refractory depressed patients yield promising results. More thorough characterisation of the underlying pathophysiology of depression including brain imaging results as well as molecular biological variables will hopefully result in further insight into of the understanding of the illness and therefore better treatment of depression.