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Diseases that affect both wild and domestic animals can be particularly difficult to prevent, predict, mitigate, and control. Such multi-host diseases can have devastating economic impacts on domestic animal producers and can present significant challenges to wildlife populations, particularly for populations of conservation concern. Few mathematical models exist that capture the complexities of these multi-host pathogens, yet the development of such models would allow us to estimate and compare the potential effectiveness of management actions for mitigating or suppressing disease in wildlife and/or livestock host populations. We conducted a workshop in March 2014 to identify the challenges associated with developing models of pathogen transmission across the wildlife-livestock interface. The development of mathematical models of pathogen transmission at this interface is hampered by the difficulties associated with describing the host-pathogen systems, including: (1) the identity of wildlife hosts, their distributions, and movement patterns; (2) the pathogen transmission pathways between wildlife and domestic animals; (3) the effects of the disease and concomitant mitigation efforts on wild and domestic animal populations; and (4) barriers to communication between sectors. To promote the development of mathematical models of transmission at this interface, we recommend further integration of modern quantitative techniques and improvement of communication among wildlife biologists, mathematical modelers, veterinary medicine professionals, producers, and other stakeholders concerned with the consequences of pathogen transmission at this important, yet poorly understood, interface.