Over the last thirty years, epidemiologic and molecular studies indicate a strong and synergist relationship between the dual epidemics of herpes simplex type 2 (HSV-2) and HIV-1 infection. While prospective studies show that HSV-2 infection increases the risk for HIV-1 acquisition by 2- to 3-fold, HSV-2 suppression with standard prophylactic doses of HSV-2 therapy did not prevent HIV-1 acquisition. Reconciling these discrepancies requires understanding recent HSV-2 pathogenesis research, which indicates HSV-2 infection is not a latent infection with infrequent recurrence but a near constant state of reactivation and viral shedding which is not completely suppressed by standard antivirals. Because current antivirals do not prevent or fully suppress HSV-2 replication, priorities are HSV-2 vaccine development and antivirals that reach high concentrations in the genital mucosa and suppress the persistent genital inflammation associated with genital herpes reactivation in order to reduce the increased susceptibility to HIV-1 infection associated with HSV-2. HIV-1 and HSV-2 synergy is also seen among co-infected individuals who exhibit higher HIV-1 viral load compared to HSV-2 uninfected individuals. Standard HSV-2 therapy modestly lowers HIV-1 viral load and is associated with slower HIV-1 disease progression. A promising area of research is higher doses of HSV-2 suppressive therapy achieving a greater reduction in plasma HIV-1 RNA, which could translate to greater reductions in HIV-1 disease progression and infectiousness. However, many questions remain to be answered including potential effectiveness and cost-effectiveness of higher dose HSV-2 suppressive therapy. Mathematical models of HSV-2 and HIV-1 at a population level would be useful tools to estimate the potential impact and cost-effectiveness of higher dose HSV-2 suppressive therapy.