Arenaviruses are a genetically diverse family of enveloped RNA viruses. A defining trait of arenaviruses is their ability to cause persistent, asymptomatic infections in their rodent hosts. Rodent reservoirs typically have high reproductive rates and dense populations, which enhance viral transmission. While rodent-to-human transmission is most common, human-to-human transmission can occur, particularly in nosocomial settings, posing a significant infection risk. Arenavirus infections in humans can result in asymptomatic infections or mild flu-like symptoms that can progress in some individuals to severe and often fatal viral hemorrhagic fever (VHF). Medical countermeasure development for arenaviruses has lagged behind advancements in molecular biology, virology, and genetics. Controlling arenaviruses requires a multipronged approach that focuses on the rodent reservoirs, transmission prevention, and supportive medical treatment. Promising vaccine and therapeutic candidates for Lassa virus and several New World arenaviruses are under development. Successful deployment will require coordinated international efforts.