New causative agents of rabies continue to emerge as shown by the recent description of four novel lyssaviruses from bats in Eurasia, Aravan (ARAV), Khujand (KHUV), Irkut (IRKV), and West Caucasian bat virus (WCBV). The effect of rabies vaccination prior to exposure to these new lyssaviruses was investigated in two animal models (i.e., Syrian hamsters and ferrets). The hamsters were vaccinated intramuscularly with a commercial human or veterinary vaccine or with an experimental vaccinia-rabies glycoprotein recombinant vaccine. At 5 weeks after vaccination, animals were challenged with ARAV, KHUV, IRKV, or WCBV, or with a traditional rabies virus of dog/coyote origin. Previously vaccinated and rabies-naive ferrets were also challenged with the four new isolates. In addition, the combined effect of rabies immunoglobulin and vaccine after exposure to the four isolates was investigated in hamsters using commercially available human products or an experimental monoclonal antibody. Results showed reduced protection with pre-exposure vaccination and with conventional rabies post-exposure prophylaxis against all four new bat viruses. In general, protection was inversely related to the genetic distance between the new isolates and traditional rabies viruses. For example, the WCBV is the most divergent of these lyssaviruses, and neither pre-exposure vaccination nor conventional post-exposure prophylaxis provided significant protection. The potential impact of these new lyssaviruses on human and domestic animal health and the impact on the putative bat reservoir populations will require further field and laboratory investigation.