The various major American and European guidelines for the treatment of depression provide similar basic principles of treatment, which include individualizing the treatment plan, preparing the patient for potential long-term treatment, providing measurement-based care, and treating to remission. While the guidelines are all evidence-based, certain factors can influence differences in specific recommendations, such as the consensus group's composition, underlying mandates, and cultural attitudes. The similarities and differences among 6 sets of guidelines from Europe and the Americas published in the past decade are reviewed here (American Psychiatric Association, British Association for Psychopharmacology, Canadian Network for Mood and Anxiety Treatments, National Institute for Health and Clinical Excellence, Texas Medication Algorithm Project, and World Federation of Societies of Biological Psychiatry). In the guidelines, mild depression has the most variance in treatment recommendations; some, but not all, guidelines suggest that it may resolve with exercise or watchful waiting, but psychotherapy or antidepressants could be used if initial efforts fail. Moderate and severe major depression carry broadly similar recommendations among the guidelines. First-line treatment recommendations for moderate major depressive disorder include antidepressant monotherapy, psychotherapy, and the combination of both. Severe depression may require the combination of an antidepressant and an antipsychotic, electroconvulsive therapy, or the combination of an antidepressant and psychotherapy. Benzodiazepines play a very limited role in the treatment of depression; if the patient has catatonic depression, acutely suicidal depression, or depression with symptoms of anxiety, agitation, or insomnia, benzodiazepines are recommended by some guidelines for short-term treatment only.