Tissue-resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8⁺ TRM, there has recently been increased interest in defining the phenotype and the role of CD4⁺ TRM in diseases. Circulating CD4⁺ T cells seed CD4⁺ TRM, but there also appears to be an equilibrium between CD4⁺ TRM and blood CD4⁺ T cells. CD4⁺ TRM are more mobile than CD8⁺ TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8⁺ TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4⁺ and CD8⁺ TRM persisting between lesions may control asymptomatic shedding through interferon-gamma secretion, although this has been more clearly shown for CD8⁺ T cells. The exact role of the CD4⁺/CD8⁺ TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4⁺ TRM have now been shown to be a major target for productive and latent infection in the cervix. In HSV and HIV co-infections, CD4⁺ TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4⁺ TRM and their induction by vaccines may help control sexual transmission by both viruses.