The serpin family of serine proteinase inhibitors plays key roles in the maintenance of mammalian homeostasis. Virus-encoded serpins disrupt the balance of mammalian proteases to facilitate virus replication in the infected host. DNA viruses, in particular members of the poxvirus family, have acquired multiple copies of the functional serpins which are essential for viral pathogenesis. Virus-encoded serpins have proven to be very effective inhibitors of host proteases and thus are very attractive candidate molecules as immunomodulatory drugs. With this chapter we explain approaches to identifying immune-modulating viral serpins.