Ectromelia virus (ECTV) is an orthopoxvirus whose natural host is the mouse; it is related closely to Variola virus, the causative agent of smallpox, and Monkeypox virus, the cause of an emerging zoonosis. The recent sequencing of its genome, along with an effective animal model, makes ECTV an attractive model for the study of poxvirus pathogenesis, antiviral and vaccine testing and viral immune and inflammatory responses. This review discusses the pathogenesis of mousepox, modulation of the immune response by the virus and the cytokine and cellular components of the skin and systemic immune system that are critical to recovery from infection.