A One Health approach considers the role of changing environments with regard to infectious and chronic disease risks affecting humans and nonhuman animals. Recent disease emergence events have lent support to a One Health approach. In 2010, the Stone Mountain Working Group on One Health Proof of Concept assembled and evaluated the evidence regarding proof of concept of the One Health approach to disease prediction and control. Aspects examined included the feasibility of integrating human, animal, and environmental health and whether such integration could improve disease prediction and control efforts. They found evidence to support each of these concepts but also identified the need for greater incorporation of environmental and ecosystem factors into disease assessments and interventions. The findings of the Working Group argue for larger controlled studies to evaluate the comparative effectiveness of the One Health approach. Recent global disease events have highlighted the increasing effects of zoonotic (transmitted from animals to humans) pathogens on human and animal health (1). It has also become evident that changes in the environment, including agricultural intensification, population growth, climate change, and human encroachment into wildlife habitats, are drivers for such zoonotic disease emergence (2,3) and that environmental contamination with toxic chemicals and other hazards threaten human and animal populations (4). The One Health approach emphasizes the relatedness of human, animal, and environmental health (5) and the importance of transdisciplinary efforts (6). The One Health approach has been recognized as a major element of disease control and prevention strategies by international agencies, including the Food and Agriculture Organization of the United Nations, the World Organisation for Animal Health, and the World Health Organization (www.who.int/influenza/resources/documents/tripartite_concept_note_hanoi/en/index.html) and by national agencies and professional groups across multiple disciplines in several countries (www.onehealthinitiative.com/supporters.php). As with any paradigm, there is a need to explore and document the comparative effectiveness of the One Health approach over conventional approaches to disease prevention and control. A recent Institute of Medicine report on microbial threats to global food safety called for "research prototypes for proof of concept validation of One Health principles as applied to food safety in the developing world, and also to public-private partnerships between government and the food industry" (7), and a US-Mexico border One Health coalition has recommended a "proof of concept project to validate a One Health approach in preparedness and response to external stakeholders" (www.oneborderonehealth.com). In the biomedical context, "proof of concept" describes evidence that a particular drug, device, treatment method, or other approach is feasible, effective, and provides added value over existing approaches. Often a proof of concept study is a pilot clinical trial that helps determine whether larger, more definitive studies are indicated. Although this proof of concept model is typical of the investigation of a new drug (8), similar methods have been used to assess the proof of concept of novel teaching methods for physicians (9), mind-body techniques for stress reduction (10), and intersectoral collaboration between health services and fire departments to prevent elderly persons from falling (11).