The literature regarding risk factors for suicidal behavior in the context of major depressive episode is reviewed. An organized framework for prevention strategies is provided. Risk factors for suicide in major depression can be organized according to whether their effect is on the threshold for suicidal acts or whether they serve mainly as triggers or precipitants of suicidal acts. For patients sufficiently depressed to present for evaluation and treatment, severity of depression is a poor guide to risk for suicidal acts. The best predictors relate to the threshold or predisposition to suicidal acts in response to major depression. Although available literature on suicidal behavior focuses on major depression in general, the findings may be usefully applied in refractory depression. Guidelines for assessment and management of suicidal behavior in major depression are offered.