Many viruses have learned to evade or subvert the host antiviral immune responses by encoding and expressing immunomodulatory proteins that protect the virus from attack by elements of the innate and acquired immune systems. Some of these viral anti-immune regulators are expressed as secreted proteins that engage specific host immune targets in the extracellular environment, where they exhibit potent anti-immune properties. We review here viral immunomodulatory proteins that have been tested as anti-inflammatory reagents in animal models of disease caused by excessive inflammation or hyperactivated immune pathways. The potential for such viral molecules for the development of novel drugs to treat immune-based or inflammatory disorders is discussed.