Introduction: Rabies is a fatal neurological disease caused by rabies virus, the prototype of the Lyssavirus genus. Rabies virus (RABV) has tropism to the central nervous system (CNS) and its ability for replication leads to rabies disease. RABV replication in the CNS of majority of mammalian species, including humans, leads to fatal encephalomyelitis. The combination of virulence and pathogenicity factors enables RABV transmission from peripheral bite site to the neurons through the neuro-muscular route and leads to infection of the spinal cord and the brain. Prophylactic or therapeutic vaccine-induced antibodies are able to prevent the virus from entering the CNS. In the absence of neutralizing antibodies induced by the vaccine, the immune system is unable to control the virus after entering the nerve cells. RABV has the innate ability to evade the host immune defense responses and is able to enhance the efficiency of its entry into nerve cells, control host immune responses, and inhibit the antiviral immune stimulation. RABV delays apoptosis by controlling the expression of its proteins and adjusts the survival of infected cells according to its metabolic requirements. These mechanisms enable RABV to escape the host immune system and to proliferate in the neuronal cells. Conclusion: This study review show the different immune mechanisms involved in clearing the CNS from RABV infection and strategies that the virus uses against the host immune system in the CNS. In addition, mechanisms that the virus uses to replicate as well as the interaction of the virus with the host immune system are discussed.