Nearly half of HIV infections in the United States are concentrated among African Americans, and over half of new HIV infections occur in the South. African Americans have poorer outcomes in the entire continua of HIV and PrEP care. Complex social, structural, and behavioral factors contribute to our nation’s alarming racial disparities in HIV infection, particularly in the Deep South. Despite the importance of faith, spirituality and religious practice in the lives of many African Americans, there has been little scientific investment exploring how African Americans’ religious participation, faith and spirituality may impact our nation’s HIV epidemic. This article summarizes the state of the science on this critical issue. We also identify opportunities for new scholarship on how faith, spirituality and religious participation may impact HIV care continuum outcomes in the South and call for greater federal research investment on these issues.