Viral pathogenesis can be defined in terms of a series of successive interactions between a virus and its target host. In order for a virus to injure a target organ such as the central nervous system (CNS), it must first enter the host animal, replicate in some primary site near its place of entry, spread from this site to the CNS and infect and injure specific populations of cells within the CNS. At each of these steps, the virus must avoid or overcome a variety of immunological and nonimmunological host defenses. It has recently become possible to begin to identify the role of specific viral genes and the proteins they encode at specific steps in the pathogenesis cycle. This review focuses on current knowledge concerning the molecular and genetic basis for the pathogenesis of viral infections of the CNS. Emphasis is placed on recent research with a wide variety of neurotropic viruses including reoviruses, bunyaviruses, lymphocytic choriomeningitis virus, rabies virus, polio virus, herpes viruses, lentiviruses, and the unconventional agents responsible for disease such as scrapie.