A synergy between HIV type-1 (HIV-1) and herpes simplex virus-2 (HSV-2) has been demonstrated in many epidemiological and clinical studies over the last decade. HIV-1 infection exacerbates the clinical impact and frequency of HSV-2 reactivation events; furthermore, HSV-2 infection exacerbates the risk of HIV acquisition and transmission and may accentuate HIV disease progression. In order to maximise the impact of existing and future therapeutic and preventive interventions, this article reviews the epidemiological, clinical and therapeutic considerations associated with episodic treatment and suppression of HSV-2 infection in HIV-infected individuals.Specifically, this article describes the current expanding epidemics of both HIV and HSV-2, and how high rates of asymptomatic herpes virus shedding contribute to the under-diagnosis and continued spread of both HSV-2 and HIV. Furthermore, multiple clinical trials have studied the efficacy and clinical utility of aciclovir and other nucleoside analogues for treating and suppressing HSV-2. We review these studies and summarise the guidelines for these regimens, particularly noting the accumulated experience documenting the utility of herpes treatment and suppression in altering the natural history of symptoms and documenting the low rate of HSV-2 drug resistance to nucleoside analogues observed after more that a decade of use. Finally, there are now also growing data describing the benefits of herpes suppression in the context of individuals co-infected with HIV/HSV-2, with additional clinical trials poised to further elucidate these issues in the near future.