Depression is a serious, often chronic disease that can be managed effectively with a chronic care model in primary care settings. Depressed persons are likely to be seen by a primary care physician, but their condition often goes unrecognized and untreated. There are effective treatment models that consist of efficacious psychotherapeutic and pharmacological interventions, use of evidence-based guidelines for primary care treatment of depression, development of explicit plans and protocols, reorganization of practice, longitudinal follow-up, patient self-management, decision-making support, access to community resources and leadership commitment. Moving these models into everyday practice requires overcoming both clinical and system barriers. Barriers consist of issues surrounding patients, providers, practices, plans, and purchasers. An understanding of these barriers at each level helps to provide a framework for the changes required to overcome them. The Robert Wood Johnson Foundation National Program on Depression in Primary Care will seek to apply simultaneously both clinical and system strategies in a new five-year initiative to overcome these barriers.