Arenaviruses merit interest as experimental model systems to study virus-host interactions and as clinically important human pathogens. Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever (HF) in humans. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen. Moreover, arenaviruses pose a biodefense threat. No licensed arenavirus vaccines are available, and current therapy is limited to the use of ribavirin, which is only partially effective and associated with significant side effects. The development of arenavirus reverse genetics systems has made it possible to manipulate the arenavirus genome, which is contributing to significant progress in understanding arenavirus molecular and cell biology, as well as arenavirus-host interactions underlying arenavirus-induced HF disease in humans. This, in turn, should facilitate the development of novel both vaccines and antiviral drugs to combat the dual threats of naturally occurring and intentionally introduced arenavirus infections.