Major depressive disorder is currently the second leading cause of disability and is projected to be the leading cause of global burden of disease by 2030. Arab healthcare practitioners face region-specific challenges that the current set of international guidelines do not address. Currently, most Middle Eastern countries are exposed to a multitude of stressors because of conflicts and wars. Consequently, there has been a rise in terrorism and fundamentalism, as well as stress-related mental health problems. A panel of experts from 22 Arab countries met to reach consensus and develop clear practice guidelines on the treatment of major depressive disorder in those countries. The guidelines are based on evaluations of evidence from the Food and Drug Administration (FDA) registration studies and regulatory approvals, as well as large, well-designed, double blind, placebo-controlled studies. Given the regional specificity of these guidelines (addressing social determinants, religious beliefs, available resources and reaction to treatment modalities), psychiatrist compliance to guidelines might increase and lead to improved patient outcomes. Members of the working group recommend that collaborative projects be developed and initiated regionally to study clinical outcomes of treatment of major depressive disorder in the Middle East.