Herpes simplex virus (HSV) is a neurotrophic virus that initially infects mucoepithelial cells and establishes latent infections in neurons from where it can be reactivated. Both primary and secondary HSV infections can be associated with morbidity and in rare cases mortality. The ability of the organism to clear herpesvirus infections is determined by a complex interplay between the virus and cells of the immune system. The leukocytes are able to restrict viral replication through a number of mechanisms including production of cytokines, chemokines, and free radicals as well as through cytotoxic activity. HSV interferes with many of these activities and hence hampers the antiviral response. Molecular understanding of the virus-cell interactions that occur between HSV and leukocytes has grown in recent years, which has allowed insight into the molecular details of viral pathology. This review presents the current knowledge about virus-cell interactions between HSV and leukocytes with special emphasis on macrophages.