The invention provides methods for identifying an anti-poxviral agents. In many embodiments, the methods involve contacting a poxviral p28 polypeptide with a candidate agent, and determining an effect of the agent on a ubiquitin ligase activity of the p28 polypeptide. The effect of the agent may be determined using a variety of different cell based or biochemical assays, such as polyubiquitylation assays and cell viability assays. The invention also provides methods for modulating poxvirus pathogenicity in a cell, and methods of treating an individual infected with a poxvirus. The subject methods find use in a variety of drug discovery, research and military applications.