Resistance to HIV-1 infection in HIV-1-exposed sero-negative (HESN) persons offers a promising opportunity to identify mechanisms of ‘natural’ protection. Unique features of the mucosa in particular may contribute to this protection. Here, we highlight several key issues pertaining to the mucosal correlates of protection in HESN persons, including humoral immune responses, mechanisms of mucosal HIV-1 neutralization, immune cell activation, and role of the microbiota in mucosal responses. We also discuss mucosal model systems that can be used to investigate the mechanisms of resistance in HESN subjects. A clear understanding of the mucosal correlates of protection against HIV-1 in HESN persons will provide critical new insights for the development of effective vaccine and microbicide strategies for the prevention of HIV-1 transmission.