HIV-1 and simian immunodeficiency virus (SIV), as well as their hosts, face perils at mucosal front lines in early infection. At these sites, 'resting' CD4⁺ memory T cells fuel infection (because they are hosts for virus), depleting CD4⁺ memory T cells throughout the lymphoid tissues, particularly in the gut, and eliciting an immunosuppressive regulatory T-cell response that impairs host defence. But HIV-1 and SIV also risk elimination at the earliest stage of infection, at the mucosal point of entry, if founder populations of infected cells do not expand sufficiently to establish a self-propagating infection. Microbicides and vaccines could increase these viral vulnerabilities at mucosal front lines.