The filoviruses, Ebola and Marburg, are two of the most pathogenic viruses, causing lethal hemorrhagic fever in humans. Recent discoveries suggest that filoviruses, along with other phylogenetically or functionally related viruses, utilize a complex mechanism of replication exploiting multiple cellular components including lipid rafts, endocytic compartments, and vacuolar protein sorting machinery. In this review, we summarize these recent findings and discuss the implications for vaccine and therapeutics development.