Herpes simplex virus (HSV) serotypes 1 and 2 establish lifelong infections that can produce reactivated pools of virus at mucosal sites where primary infections were initiated. No approved vaccines are available. To break the transmission cycle, interventions must either prevent infection or reduce infectivity at mucosal sites. This article discusses the recent experimental successes of immunoprophylactic and therapeutic compounds that enhance resistance and/or reduce viral loads at genital and ocular mucosa. Current data indicate Toll-like receptor agonists and selected immunomodulating compounds effectively increase the HSV infection threshold and hold promise for genital prophylaxis. Similarly, immunization at genital and extragenital mucosal sites is discussed. Finally, preclinical success with novel immunotherapies for ocular HSV that address herpetic keratitis and corneal blindness is reviewed.