Rodents are the most abundant order of living mammals, distributed on every continent except Antarctic and represent 43 % of all mammalian species. Beside causing food losses and infrastructural damage, rodents can harbour pathogens that may cause serious problems to human and animal health. Unfortunately, rodent-associated problems are not an issue of the past as some may have thought, even not in the developed world. This chapter describes four factors that determine the risk and severity of human infection by zoonotic pathogens of rodents: human behaviour, human health condition, rodent ecology & behaviour and pathogen ecology & persistence. It provides an overview of these factors, their interrelation and also some directions for further research. Main conclusion of this chapter is that although science has come a long way already and we have won some small victories over the rodents, the game of cat (i.e. humans) and mouse is far from being settled.The order of Rodentia is the most abundant and diversified order of living mammals and represents in total about 43 % of all mammalian species (Wilson and Reeder 1993;Huchon et al. 2002). Rodents are distributed on every continent except Antarctica and include many of the most abundant mammals. For many centuries, opportunistic rodent species have been considered as serious pests because of the damage they cause to crops, stored produce or infrastructure and the role they play in the transmission of pathogens to humans and livestock. Improved public sanitation conditions like safe drinking water, the introduction of sewers and the development of efficient anticoagulant rodenticides in the 1950s resulted in an improved public health situation and created the illusion that rodent-associated problems in the developed world had become an issue of the past.More recently, however, the concern about rodents in both the developing and developed world has grown again because of various reasons. These reasons are the following:629