Lassa virus (LASV), the most dangerous human pathogen among the Arenaviridae, belongs to a complex of genetically related virus strains responsible for the deaths of thousands of people in West Africa each year. The virus has a bi-segmented (L and S) single-stranded RNA genome. Each segment contains two genes in ambisense orientation. The L RNA encodes a large protein, L, or RdRp and a small zinc-binding, Z protein. The S RNA encodes the major structural proteins, nucleoprotein (NP) and glycoprotein precursor (GPC), cleaved into signal peptide, GP1, and GP2 glycoproteins. Genetic diversity among LASV strains is the highest within the family Arenaviridae and NP and RdRp genes are the most variable among LASV genes. The LASV genetic diversity is a great challenge for vaccine development. In addition to LASV and the prototype lymphocytic choriomeningitis virus (LCMV), the Old World group of arenaviruses includes three other related viruses, Mopeia (MOPV), Mobala (MOBV), and Ippy (IPPYV). These viruses as well as a MOP/LAS reassortant carrying the L RNA segment from MOPV and S RNA segment from LASV are non-pathogenic for experimental animals and are able to induce protective immunity against LASV. Lassa Fever pathogenesis is a sum of the effects induced by viral replication and immune response. The goal of this review is to cover recent publications on viral and host genes that control LASV virulence. The full-length genome sequence of LASV isolates and LASV-related nonpathogenic arenaviruses will provide a useful genetic tool to map LASV genes involved in virulence and to gain insight into phylogeny and evolution of the Old World arenaviruses.