: Reovirus (respiratory enteric orphan virus), a naturally occurring benign human pathogen, has an inherent ability to target transformed and cancerous cells and cause their lysis, while leaving non-transformed cells relatively unaffected. The efficiency of this innate oncolytic activity of reovirus correlates with expression of the ras oncogene. Cells expressing activated Ras and the related Ras/RalGEF/p38 pathway are more permissive to the reovirus infection than that of untransformed counterparts. Ras-transformation orchestrates selective oncolysis of cancerous cells by mediating efficient virus uncoating as well as by enhancing infectivity and subsequent apoptosis-dependent release of nascent virus particles. Different human and murine cell lines derived from naturally occurring tumors also display similar activation of the ras pathway, and thus present selective susceptibility to reovirus oncolysis under in vitro as well as in vivo conditions. This ability of reovirus to selectively target a wide variety of tumors offers a novel anti-cancer therapeutic option. However, the efficiency of reovirus virotherapy in immunocompetent hosts is compromised due to the presence of anti-viral innate and adaptive immune responses. Hence, the success of this highly promising reovirus oncolytic therapy will likely be enhanced by modulating host immunity.