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The arenaviruses are a large and diverse family of viruses that merit significant attention as powerful models for experimental virology and as important human pathogens. Over the past decades several arenaviruses have emerged as causative agents of severe viral hemorrhagic fevers that belong to the most devastating human diseases and cause considerable suffering in many countries of the Developing World. The Old World arenavirus Lassa virus is the most prevalent human pathogen among the arenaviruses with several hundred thousand infections per year in Africa with thousands of deaths. The South American hemorrhagic fever viruses Junin, Machupo, Guanarito, and Sabia have emerged as etiological agents of severe hemorrhagic fevers in Latin America. There is no licensed vaccine available and therapeutic options are restricted, resulting in 15-30% mortality in hospitalized patients. New pathogenic arenaviruses emerge with on average one new species being discovered every three years, representing a serious concern for public health.The past years have seen rapid progress in many aspects of arenavirus research. The present Special Issue covers major recent developments in molecular arenavirus virology, fundamental mechanisms of arenavirus-host cell interaction, and the development of novel anti-viral strategies against these important pathogens.