The number of available antidepressant medications has increased dramatically in the last 10 years. Furthermore, no single medication is a panacea for all depressed patients-a fact underscored by randomized, controlled trial evidence showing that when one medication fails, an alternative may succeed. Thus, a key issue in the treatment of depression is how to optimally orchestrate available medication options to maximally benefit the greatest number of patients most rapidly. One approach is the use of consensus guidelines or medication algorithms. This paper discusses the rationale for and critical issues in the development of medication algorithms, and the timely use of symptom measures to ensure proper implementation. Once developed, guidelines must be appropriately implemented by clinicians, adhered to by patients, and supported by administrators. These three stakeholder groups often need education, incentives, and ongoing support to implement such guidelines. Whether guidelines actually improve outcome is largely uninvestigated, although a recent study of depressed patients in primary care found that using guidelines did improve outcome but at an increased treatment cost. The clinical and economic impact of guideline-driven treatment for the severe and persistently depressed deserves study.