The comparative medicine approach, as applied to the study of laboratory animals for the betterment of human health, has resulted in important medical and scientific progress. Much of what is known about the human health risks of many toxic and infectious hazards present in the environment derives from experimental studies in animals and observational (epidemiological) studies of exposed human populations. Yet there is a third source of "in vivo" knowledge about host-environment interactions that may be underused and -explored: the study of diseases in naturally occurring animal populations that may signal potential human health threats. Just as canaries warned coal miners of the risk of toxic gases, other nonhuman animals, due to their greater susceptibility, environmental exposure, or shorter life span, may serve as "sentinels" for human environmental health hazards. Traditionally, communication between human and animal health professionals about cross-species sentinel events has been limited, but progress in comparative genomics, animal epidemiology, and bioinformatics can now provide an enhanced forum for such communication. The "One Health" concept involves moving toward a comparative clinical approach that considers "shared risks" between humans and animals and promotes greater cooperation and collaboration between human and animal health professionals to identify and reduce such risks. In doing so, it also creates new opportunities for the field of comparative medicine that can supplement traditional laboratory animal research.