The majority of newly emerging diseases are zoonoses caused by pathogens transmitted directly or indirectly through arthropod vectors to humans. Transmission chains leading to human infection frequently involve intermediate vertebrate hosts, including wildlife and domestic animals. Animal-based surveillance of domestic and wild animals for zoonotic pathogens is a global challenge. Until recently, there has been no scientific, social, or political consensus that animal-based surveillance for zoonotic pathogens merits significant infrastructural investment, other than the fledgling efforts with avian influenza. National institutions charged with strategic planning for emerging diseases or intentional releases of zoonotic agents emphasize improving diagnostic capabilities for detecting human infections, modifying the immune status of human or domestic animals through vaccines, producing better antiviral or antibacterial drugs, and enhancing human-based surveillance as an early warning system. With the exception of human vaccination, these anthropocentric approaches target post-spillover events, and none of these avenues of research will reduce the risk of additional emergences of pathogens from wildlife. Novel schemes for preventing spillover of human pathogens from animal reservoir hosts can spring only from an understanding of the ecological context and biological interactions that result in zoonotic disease emergence. Although the benefits derived from investments to improve surveillance and knowledge of zoonotic pathogens circulating among wildlife reservoir populations are uncertain, our experience with human immunodeficiency virus and the pandemic influenza inform us of the outcomes that we can expect by relying on detection of post-spillover events among sentinel humans. Mt Sinai J Med 76:421-428, 2009. (c) 2009 Mount Sinai School of Medicine.