© Springer International Publishing Switzerland 2016. The nervous system, endocrine system, and immune system are highly connected and affect the outcome of viral infections. This chapter introduces a brief history of the field of psychoneuroimmunology and then provides examples of the impact of stress on two neurotropic viral infections: herpes simplex and Theiler’s virus. Psychological stress has been implicated in the development and progression of multiple sclerosis (MS), and one of the best models for studying the pathogenesis of MS is Theiler’s virus infection in mice. Three stress paradigms were investigated in Theiler’s virus infection: restraint stress, social stress, and maternal separation stress. Generally these stressors were shown to decrease both the innate and adaptive immune response following Theiler’s virus infection through the increased production of glucocorticoids. The stress-induced immunosuppression results in increased viral titers in the central nervous system and increased inflammatory demyelination. In conclusion, stress at the time of infection with a neurotropic virus results in decreased immune response to the virus and increased viral replication in the CNS, which in turn leads to more severe chronic inflammatory disease.