Poxviruses are large cytoplasmic DNA viruses that cause significant human and veterinary diseases. Vaccinia virus, the laboratory prototype for the poxvirus family, has a 200-year history of intentional human infection via skin scarification for smallpox vaccination. Eczema vaccinatum is a major severe complication of smallpox vaccination in people with atopic dermatitis. Life-threatening progressive vaccinia occurs in patients with T cell immunodeficiency. Understanding poxviral pathogenesis and its interface with the host immune system is a prerequisite to the development of safer and better poxvirus-based vaccine and therapeutic strategies. We are taking a multidisciplinary approach that integrates virology, immunology, and cell biology to address poxvirus and host interactions at both cellular and organismal levels. We take advantage of the genetic systems of the host and the virus to address the role of an antiviral sensing pathway in host defense and the mechanisms of viral immune evasion.