The Old World tropical and subtropical frugivorous bat genus Rousettus (Pteropodidae) contains species with broad distributions, as well as those occurring in restricted geographical areas, particularly islands. Herein we review the role of Rousettus as a keystone species from a global "One Health" approach and related to ecosystem functioning, zoonotic disease and public health. Rousettus are efficient at dispersing seeds and pollinating flowers; their role in forest regeneration is related to their ability to fly considerable distances during nightly foraging bouts and their relatively small body size, which allows them to access fruits in forested areas with closed vegetation. Rousettus are also reservoirs for various groups of pathogens (viruses, bacteria, fungi, protozoa), which, by definition, are infectious agents causing disease. The study of day roosts of different species of Rousettus and the successful establishment of captive breeding colonies have provided important details related to the infection dynamics of their associated pathogens. Large-scale conversion of forested areas into agricultural landscapes has increased contact between humans and Rousettus, therefore augmenting the chances of infectious agent spillover. Many crucial scientific details are still lacking related to members of this genus, which have direct bearing on the prevention of emerging disease outbreaks, as well as the conservation of these bats. The public should be better informed on the capacity of fruit bats as keystone species for large scale forest regeneration and in spreading pathogens. Precise details on the transmission of zoonotic diseases of public health importance associated with Rousettus should be given high priority.