Major depression is one of the most common diseases in the field of psychiatry yet it may also occur accompanying variety of other medical conditions.It is a brain disease with multiple etiologies which may or may not being interacting with each other to precipitate an episode of depression.It relatively fits to biopsychosocial model type pathogenesis.Most recent findings on pathogenesis of depression are presented.From the earliest primitive models to the our best understanding in 21th century.Different mechanisms that might lead to major depression are discussed.Furthermore,most recent guidelines for first line therapy as well as newest treatment approaches with their detailed modes of actions are substantiated.