African Americans have been underrepresented in clinical trials. This study was designed to determine factors that may help explain the low participation rate of African Americans in clinical trials. A historical review documented past medical experimentation and other practices on blacks that were often brutal and unethical. These experiences may have served to fortify the legacy of African-American mistrust in the medical system and culminated in the infamous Tuskegee Syphilis Study. Four major barriers to participation in clinical trials were identified: lack of awareness about trials, economic factors, communication issues, and mistrust. These barriers, as well as others, can be surmounted with proper pretrial planning, patient education, genuine commitment and concern by study staff, and hard work to overcome deficiencies.