Pre-exposure prophylaxis (PrEP) has promise for reducing racial/ethnic HIV disparities; yet, acceptance among African Americans remains low. PrEP-related stigmas may impact uptake, but this is understudied. This study examines mechanisms by which stigma impacts PrEP acceptance among various priority African American populations. Focus group data from 63 African American young adults (aged 18-29 years) in Louisville, Kentucky, explore how various stigmas impact attitudes toward PrEP. Data were analyzed using grounded theory analytic techniques. PrEP stigma, HIV stigma, sexual behavior stigma, and homophobia/transphobia individually reduce PrEP uptake. These stigmas also interact synergistically to undermine PrEP acceptance. Key challenges resulting from various stigmas and their interactions include medical hesitancy, lack of perceived susceptibility based on gender and sexuality, the role of gender norms in HIV prevention, and deprioritizing HIV prevention due to social rejection. Interventions to increase awareness, destigmatize PrEP, remediate social marginalization related to identity, HIV status, and gendered perceptions of sexual risk, as well as more focus on diverse priority groups, are needed to present PrEP as a viable HIV prevention option for African American communities. More research is needed to optimize strategies that address stigma and increase acceptance of novel HIV prevention technologies.