Herpes simplex virus (HSV) is a large DNA virus with unique properties that can be exploited for in vivo gene therapy. HSV is neurotropic, establishes latency, and has a large transgene capacity. These properties can be utilized in therapy of nervous system diseases. Wild-type HSV and the vectors derived from it induce both innate and acquired immune response. However, HSV is skillful in escaping the host response. It has evoked mechanisms including avoidance of antigen presentation on major histocompatibility (MHC) molecules, inhibition of host interferon response, impairment of the antibody and complement responses, and inhibition of apoptosis in infected cells. One of the molecules affecting the interferon response is ICP34.5, encoded by the so-called neurovirulence gene γ134.5. The mutants deleted of this gene are non-neurovirulent, having ca 3000-fold decreased ability to replicate in CNS. The HSV vectors based on the γ134.5 deletion mutants show efficacy against glioma and in other cancer therapies. These mutants provide an interesting platform for developing safe and efficient gene delivery for numerous neurological diseases or brain tumors. The immune response evoked by the HSV vector is central in determining the spread and persistence of the vector, and its transgene expression, and in controlling the innate and adaptive immune response against effective spread of the vector. These questions are key issues of herpesviral gene therapy and cancer therapy at the moment. This review describes the involvement of immune response in HSV infection and in γ134.5 deletion HSV-based virotherapy. We discuss the challenge of developing vectors with desired immune response benefiting the therapy and maintaining the efficiency.