Serine proteinase inhibitors, also called serpins, are an ancient group ing of proteins found in primitive organisms from bacteria, protozoa and horseshoe crabs and thus likely present at the time of the dinosaurs. up to all mammals living today. The innate or inflammatory immune system is also an ancient metazoan regulatory system. providing the first line ofdefense against infection or injury. The innate inflammatory defense response evolved long before acquired. antibody dependent immunity. Viruses have developed highlyeffective stratagems that undermine and block a wide variety ofhost inflammatory and immune responses. Some of the most potent of these immune modifying strategies utilize serpins that have also been developed over millions ofyears. including the hijacking by some viruses for defense against host immune attacks . Serpins represent up to 2-10 percent ofcirculating plasma proteins. regulating actions as wide ranging as thrombosis. inflammation. blood pressure control and even hormone transport. Targeting serpin-regulated immune or inflammatory pathways makes evolutionary sense for viral defense and many of these virus-derived inh ibitory proteins have proven to be highly effective.working at very low concentrations-even down to the femptomolar to picomolar range. We are studying these viral anti-inflammatory proteins as a new class ofimmunomodulatory therapeutic agents derived from their native viral source. One such viral serpin, Serp-I is now in clinical trial (conducted by VIRON Therapeutics, Inc.) for acute unstable coronary syndromes (unstable angina and small heart attacks), representing a 'first in class' therapeutic study. Several other viral serpins are also currently under investigation as anti-inflammatory or anti-immune therapeutics. This chapter describes these original studies and the ongoing analysis ofviral serpins as a new class ofvirus-derived immunotherapeutic.