© 2018 Whitley R and Baines J. Infection with herpes simplex virus (HSV) types 1 and 2 is ubiquitous in the human population. Most commonly, virus replication is limited to the epithelia and establishes latency in enervating sensory neurons, reactivating periodically to produce localized recurrent lesions. However, these viruses can also cause severe disease such as recurrent keratitis leading potentially to blindness, as well as encephalitis, and systemic disease in neonates and immunocompromised patients. Although antiviral therapy has allowed continual and substantial improvement in the management of both primary and recurrent infections, resistance to currently available drugs and long-term toxicity pose a current and future threat that should be addressed through the development of new antiviral compounds directed against new targets. The development of several promising HSV vaccines has been terminated recently because of modest or controversial therapeutic effects in humans. Nevertheless, several exciting vaccine candidates remain in the pipeline and are effective in animal models; these must also be tested in humans for sufficient therapeutic effects to warrant continued development. Approaches using compounds that modulate the chromatin state of the viral genome to suppress infection and reactivation or induce enhanced antiviral immunity have potential. In addition, technologies such as CRISPR/Cas9 have the potential to edit latent viral DNA in sensory neurons, potentially curing the neuron and patient of latent infection. It is hoped that development on all three fronts—antivirals, vaccines, and gene editing—will lead to substantially less HSV morbidity in the future.