To review recent findings on the epidemiology, burden, diagnosis, comorbidity, and treatment of depression, particularly in general medical settings; to delineate barriers to the recognition, diagnosis, and optimal management of depression in general medical settings; and to summarize efforts under way to reduce some of these barriers. MEDLINE searches were conducted to identify scientific articles published during the previous 10 years addressing depression in general medical settings and epidemiology, co-occurring conditions, diagnosis, costs, outcomes, and treatment. Articles relevant to the objective were selected and summarized. Depression occurs commonly, causing suffering, functional impairment, increased risk of suicide, added health care costs, and productivity losses. Effective treatments are available both when depression occurs alone and when it co-occurs with general medical illnesses. Many cases of depression seen in general medical settings are suitable for treatment within those settings. About half of all cases of depression in primary care settings are recognized, although subsequent treatments often fall short of existing practice guidelines. When treatments of documented efficacy are used, short-term patient outcomes are generally good. Barriers to diagnosing and treating depression include stigma; patient somatization and denial; physician knowledge and skill deficits; limited time; lack of availability of providers and treatments; limitations of third-party coverage; and restrictions on specialist, drug, and psychotherapeutic care. Public and professional education efforts, destigmatization, and improvement in access to mental health care are all needed to reduce these barriers.