Genetically engineered mice with targeted mutations in genes encoding immunologically relevant molecules were used to elucidate the role of different immune effector mechanisms in protection against a rabies virus (RV) infection. In vaccinated animals challenged with a highly virulent strain of RV, antibodies were crucial in protection. In naive mice challenged with an attenuated strain of the virus that does not cause disease in adult fully immunocompetent mice but kills RAG mice that lack functionally active T and B cells, different immune effector mechanisms were shown to suffice for protection.