Publisher Summary Rabies is a unique neurological infection that can be prevented by post-exposure vaccination, at least when the vaccine is administered to patients within a reasonable period of time after a rabies exposure. Thus, vaccine efficiency can be conferred by immunization even after the virus enters the body and reaches the nervous system. Because of the ability of rabies virus to impair immune responsiveness, it is intriguing to understand how immunization against rabies can prevent or limit virus progression toward and/or through the nervous system. In this chapter, the mechanisms involved in specific immune responses as well as the molecular basis of rabies vaccine protection are discussed. Today, with an increased understanding of the particular properties of rabies virus infection, one can propose a biological relevance and rationale for heuristic choices elaborated by former vaccine designers. On the other hand, the success of vaccination of patients after exposures urges to investigate further the mechanisms that sustain the immune B cell response despite the impermeability of the blood-brain barrier to most antibodies.