Several mammarenaviruses are responsible of causing severe hemorrhagic fever (HF) diseases associated with high morbidity and mortality, representing an important threat to humans living in these viral endemic regions. Currently, there are no US Food and Drug Administration (USFDA)-approved vaccines available to prevent mammarenavirus infections, and therapeutic treatment is limited to an off-label use of ribavirin for which efficacy remains controversial and can also cause significant side effects. Vaccination is the most effective way to prevent viral diseases, with live-attenuated vaccines (LAVs) providing robust and long-term protection against subsequent natural infection by the corresponding virulent form of the viruses. Reverse genetics approaches have provided researchers with the unique opportunity to investigate different aspects of the biology of mammarenavirus and to generate recombinant viruses containing predetermined mutations in their viral genome to dissect mechanisms of viral replication and pathogenesis in cell cultured and validated animal models of infection. Importantly, these reverse genetics tools have also allowed the rational generation of attenuated forms of the viruses for their potential implementation as LAVs for the prevention of diseases caused by mammarenavirus infections. Here, we describe plasmid-based reverse genetic approaches and different strategies to generate attenuated recombinant mammarenaviruses for their potential implementation of LAVs to combat these important human pathogens.