Lassa fever virus infection can lead to severe and sometime fatal hemorrhagic fever diseases in humans, for which there is no vaccine or effective drug. Studies of Lassa (LASV) and other pathogenic arenaviruses have been hindered by the strict requirement for BSL-4 containment to work with these select agents. We have developed an infectious molecular clone for a prototypic BSL2 arenavirus (Pichinde virus) as well as a safe and convenient surrogate animal model for LASV. These novel systems have afforded us with unique resources and unprecedented opportunities to investigate in details the processes of viral entry/infection, genome replication/transcription and virulence. We are also interested in characterizing novel mechanisms of host innate-immune suppression by these viruses. These efforts may lead the development of effective therapeutics against this deadly viral pathogen.