Prevalence and transmission rates of rodent-borne viruses within host populations vary in time and space and among host-virus systems. Improving our understanding of the causes of these variations will lead to a better understanding of changes in disease risk to humans. The regulators of prevalence and transmission can be categorized into five major classes: (1) Environmental regulators such as weather and food supply affect transmission rates through their effect on reproductive success and population densities. (2) Anthropogenic factors, such as disturbance, may lead to ecosystem simplification and decreased diversity. These changes favor opportunistic species, which may serve as reservoirs for zoonotic viruses. (3) Genetic factors influence susceptibility of mice to infection or capacity for chronic shedding and may be related to population cycling. (4) Behavioral factors, such as fighting, increase risk of transmission of some viruses and result in different patterns of infection between male and female mice. Communal nesting may result in overwinter transmission in colder climates. (5) Physiologic factors control host response to infection and length of time the host remains infectious. Risk prediction is difficult because these regulators are numerous and often interact, and the relative importance of each varies according to the host species, season, year, and geographic location.