Herpes simplex virus types 1 and 2 (HSV-1 and -2) are two of the major opportunistic agents involved in the pathogenesis of AIDS, which is caused by human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). A body of evidence suggests that they can also act as co-factors by interacting with HIV-1, thereby influencing disease progression. Indeed, the HIV-1 life cycle can be affected by HSV at different levels of interaction, both in vitro and in vivo: (i) transactivation of the HIV-1 long terminal repeat can be mediated, probably through different pathways, by HSV-1-infected cell protein (ICP)0, ICP4, ICP27 and US11 gene products; the HSV-1 transactivator viral protein 16 is not able to transactivate the long terminal repeat; (ii) cytokine release and antigen presentation from HSV-infected cells are both able to stimulate HIV-1 expression; (iii) Pseudotyping of the HIV-1 core particle with HSV-1 envelope glycoproteins can expand HIV-1 tropism to new cell types. Moreover, in vivo studies report that aciclovir treatment can produce a survival benefit in HIV-1-infected patients and that recurrent genital herpes appears to be linked to HIV-1 transmission by both boosting plasma retroviral load and providing a portal of entry and exit for HIV-1.