Chronic pain is a major health concern with up to 50% of patients finding little if any relief following traditional pharmacotherapy. This review describes the treatment of chronic pain using herpes simplex virus type 1 (HSV)-based vectors. HSV can be effectively used to deliver pain-modulating transgenes to sensory neurons in vivo following intradermal inoculation. The vector genome persists in peripheral nerve bodies in an episomal state and serves as a platform for expression of natural pain-relieving molecules that access endogenous antinociceptive circuitry. The vectors are mutated to prevent reactivation from latency or spread to the central nervous system. Dermatome selection for administration of HSV vectors provides targeted delivery of pain gene therapy to primary afferent neurons. This novel approach alleviates pain without systemic side effects or the induction of tolerance and can be used in combination with standard pain treatments.