The Arenaviruses are structurally quite simple, consisting of only four primary gene products encoded on two RNA strands. Despite this very simple genetic plan, these viruses are capable of interacting with the host in a bewildering variety of permutations that result in a range of infections from a lifelong persistent carrier state, as is evident in the neonatally or congenitally infected carrier mouse, to the lethal acute diseases typical of Lassa, Machupo, Junin, and other arenavirus hemorrhagic fevers. These differing disease courses are, in part, determined by the clash of two factors: the cellular and tissue site(s) of virus replication in vivo, defined as tropism, and the genetically determined host response to the infecting virus. When the virus replicates in critical tissues like the meninges and choroid plexi of the mouse brain, as is the case in acute LCMV infection, and the host is capable of mounting a strong T-cell response, the end result is a fatal choriomeningitis (Fig. 1). However, replication of the virus in these same tissues results in little tissue injury or disease in a mouse that has been immunosuppressed, or in a neonate prior to maturation of the T-cell response. This immunopathological paradox is at the core of understanding the pathogenesis of LCM disease and has provided a singularly important biological model for probing cellular immunology for more than six decades (Buchmeier and Zajac 1999). In this brief chapter, the nature of the arenavirus proteins and their functions will be discussed with particular emphasis on their role in infection and disease.