Depression is a common mental disorder that presents with depressed mood. It can become chronic or recurrent and lead to substantial impairment in an individual's ability to function. At this level, it is identified as major depressive disorder (MDD). Depression and MDD occur across all racial and ethnic groups. Although many depressed patients are treated in primary care, depression in these settings has been underdetected and undertreated. African Americans, especially, who suffer from depression are frequently underdiagnosed and inadequately managed in primary care due to patient, physician, and treatment setting factors. Patient factors include being poor, uninsured, restrictive insurance policies, biological-genetic vulnerability, nonresponsiveness to traditional pharmacological interventions, and stigma (i.e., attitudes and perceptions of mental illness). Physician factors include diagnosis and assessment, physician characteristics, physician bias, and culture; and treatment setting factors include systemic variables such as lack of or poor access to health care, racism, environment, and patient management. African Americans are less likely to receive proper diagnosis and treatment, more likely to have depression for long periods of time, and more likely to suffer greater disability from depression. Understanding patient, physician, and treatment setting factors as contributing barriers that impede effective diagnosis and treatment of depression and MDD in African Americans is critical to effective patient management and discovery. Greater African American participation in clinical research trials also is needed to effectively improve, diagnose, and treat depression in African Americans. This article examines depression among African Americans in the context of gender, culture, and psychosocial determinants, and their engagement in clinical trials.