This study explores the barriers to research participation among African American adults, focusing on mistrust of the healthcare system and research institutions. The research involved 70 participants in 11 focus groups, with a mix of individuals with and without prior research experience. Mistrust was identified as a primary barrier, rooted in historical events like the Tuskegee syphilis study and reinforced by ongoing systemic issues. Participants expressed deep-seated mistrust, influenced by past experiences of deception and discrimination, and a belief that research findings often benefit others rather than the African American community. Fear of research participation, inadequate information, and logistical concerns were also significant barriers. Participants emphasized the emotional and historical impact of past injustices, including the Tuskegee study, which continues to shape their views on medical research. They also highlighted the lack of trust in the federal government and the healthcare system, as well as the perception that research is often conducted for profit rather than for the benefit of all. Despite these barriers, many African Americans recognize the value of research and the potential for new treatments. The study underscores the need for strategies to build trust and improve participation, including community-based participatory research, culturally competent communication, and long-term partnerships. The findings highlight the complex nature of mistrust and its impact on research participation, emphasizing the importance of addressing historical and ongoing disparities to improve health outcomes for African Americans.This study explores the barriers to research participation among African American adults, focusing on mistrust of the healthcare system and research institutions. The research involved 70 participants in 11 focus groups, with a mix of individuals with and without prior research experience. Mistrust was identified as a primary barrier, rooted in historical events like the Tuskegee syphilis study and reinforced by ongoing systemic issues. Participants expressed deep-seated mistrust, influenced by past experiences of deception and discrimination, and a belief that research findings often benefit others rather than the African American community. Fear of research participation, inadequate information, and logistical concerns were also significant barriers. Participants emphasized the emotional and historical impact of past injustices, including the Tuskegee study, which continues to shape their views on medical research. They also highlighted the lack of trust in the federal government and the healthcare system, as well as the perception that research is often conducted for profit rather than for the benefit of all. Despite these barriers, many African Americans recognize the value of research and the potential for new treatments. The study underscores the need for strategies to build trust and improve participation, including community-based participatory research, culturally competent communication, and long-term partnerships. The findings highlight the complex nature of mistrust and its impact on research participation, emphasizing the importance of addressing historical and ongoing disparities to improve health outcomes for African Americans.