Concerns over the potential use of variola virus as a biological weapon have prompted new interest in the development of small molecule therapeutics to prevent and treat smallpox infection. Since smallpox is no longer endemic, human clinical trials designed to link antiviral efficacy to clinical outcome have been supplanted by antiviral efficacy evaluations in animal models of orthopoxvirus disease. This poses a unique challenge for drug development; how can animal efficacy data with a surrogate virus be used to establish clinical correlates predictive of human disease outcome? This review will examine the properties of selected animal models that are being used to evaluate poxvirus antivrial drug candidates, and discuss how data from these models can be used to link drug efficacy to clinical correlates of human disease.