The filoviruses, Ebola and Marburg, cause severe hemorrhagic fever in humans and nonhuman primates, with high mortality rates. Although the filovirus replication pathway is now understood in considerable detail, no antiviral drugs have yet been developed that directly inhibit steps in the replication cycle. One potential target is the filovirus VP40 matrix protein, the key viral protein that drives the budding process, in part by mediating specific virus-host interactions to facilitate the efficient release of virions from the infected cell. This review will summarize current knowledge of key structural and functional domains of VP40 believed to be necessary for efficient budding of virions and virus-like particles. A better understanding of the structure and function of these key regions of VP40 will be crucial, as they may represent novel and rational targets for inhibitors of filovirus egress.